EP1619199B1 - Glycolipid derivatives, process for production of the same, intermediates for synthesis thereof, and process for production of the intermediates - Google Patents
Glycolipid derivatives, process for production of the same, intermediates for synthesis thereof, and process for production of the intermediates Download PDFInfo
- Publication number
- EP1619199B1 EP1619199B1 EP04710993.9A EP04710993A EP1619199B1 EP 1619199 B1 EP1619199 B1 EP 1619199B1 EP 04710993 A EP04710993 A EP 04710993A EP 1619199 B1 EP1619199 B1 EP 1619199B1
- Authority
- EP
- European Patent Office
- Prior art keywords
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- compound
- substituted
- unsubstituted
- disease
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical class O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 title abstract description 58
- 230000015572 biosynthetic process Effects 0.000 title abstract description 52
- 239000000543 intermediate Substances 0.000 title abstract description 5
- 238000000034 method Methods 0.000 title description 60
- 150000001875 compounds Chemical class 0.000 claims abstract description 219
- 125000003118 aryl group Chemical group 0.000 claims abstract description 23
- 229930186217 Glycolipid Natural products 0.000 claims abstract description 21
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 20
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims description 12
- 208000023275 Autoimmune disease Diseases 0.000 claims description 11
- 108090000695 Cytokines Proteins 0.000 claims description 10
- 102000004127 Cytokines Human genes 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- 210000000447 Th1 cell Anatomy 0.000 claims description 7
- 125000003368 amide group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 208000023328 Basedow disease Diseases 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 201000006417 multiple sclerosis Diseases 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 208000024891 symptom Diseases 0.000 claims description 6
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 claims description 4
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- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
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- 208000015023 Graves' disease Diseases 0.000 claims description 3
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 3
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- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 3
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 3
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims description 3
- 208000016644 chronic atrophic gastritis Diseases 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 claims description 3
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 208000007475 hemolytic anemia Diseases 0.000 claims description 3
- 206010028417 myasthenia gravis Diseases 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000003113 cycloheptyloxy group Chemical group C1(CCCCCC1)O* 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 abstract description 12
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 abstract description 10
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 abstract description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 6
- 238000010189 synthetic method Methods 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 70
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 24
- 238000000746 purification Methods 0.000 description 23
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- YGOYMNMFBVUFOH-UHFFFAOYSA-N nonane-1,1,4-triol Chemical compound CCCCCC(O)CCC(O)O YGOYMNMFBVUFOH-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- -1 alkylsulfonyl halide Chemical class 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 239000011734 sodium Substances 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- 239000008096 xylene Substances 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000012442 inert solvent Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- 239000000463 material Substances 0.000 description 11
- 238000001953 recrystallisation Methods 0.000 description 11
- VQFKFAKEUMHBLV-BYSUZVQFSA-N 1-O-(alpha-D-galactosyl)-N-hexacosanoylphytosphingosine Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@H]([C@H](O)[C@H](O)CCCCCCCCCCCCCC)CO[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQFKFAKEUMHBLV-BYSUZVQFSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 229960004132 diethyl ether Drugs 0.000 description 10
- 238000007430 reference method Methods 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
- 108010074328 Interferon-gamma Proteins 0.000 description 7
- 108090000978 Interleukin-4 Proteins 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 0 *C[C@]1OC(*)(*)O[C@]1CCOC1OC(C*)C(*)C(*)C1* Chemical compound *C[C@]1OC(*)(*)O[C@]1CCOC1OC(C*)C(*)C(*)C1* 0.000 description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- 102100037850 Interferon gamma Human genes 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
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- 125000006239 protecting group Chemical group 0.000 description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 238000006359 acetalization reaction Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 229940125782 compound 2 Drugs 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 210000000581 natural killer T-cell Anatomy 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000011736 potassium bicarbonate Substances 0.000 description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 5
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- FSWCCQWDVGZMRD-UHFFFAOYSA-N 4-methylcyclohexene Chemical compound CC1CCC=CC1 FSWCCQWDVGZMRD-UHFFFAOYSA-N 0.000 description 4
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- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
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- 239000012267 brine Substances 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 4
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 4
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
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- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 4
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 4
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- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 4
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- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 3
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- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 3
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- 125000002524 organometallic group Chemical group 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
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- 230000001681 protective effect Effects 0.000 description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
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- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P17/00—Drugs for dermatological disorders
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- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/28—Radicals substituted by nitrogen atoms
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
Definitions
- the present invention relates to novel glycolipid derivatives.
- autoimmune diseases for example, multiple sclerosis, myasthenia gravis, chronic rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, systemic scleroderma, insulin-dependent diabetes, idiopathic thrombocytopenic purpura, Hashimoto's thyroiditis, Basedow's disease (Graves' disease), pernicious anemia, Addison's disease, atrophic gastritis, hemolytic anemia, ulcerative colitis, etc. are known.
- T-cells For treatment of autoimmune diseases, steroid hormones, immunosuppressants, etc. are widely used, but at the time of use, sufficient cautions are required over side-effects. Safety and highly effective drug has not yet been found.
- the cause of autoimmune diseases the involvement of T-cells has been pointed out. This is believed to arise when the helper T-cell type 1 (Th1)/helper T-cell type 2 (Th2) immune balance is lost.
- Th1 helper T-cell type 1
- Th2 helper T-cell type 2
- Th1/Th2 immune balance toward Th1 bias may be considered to play a central role ( P. Kidd, Altern. Med. Rev. 2003, 8, 223 : Takashi Yamamura, Notoshinkei, 2001, 53, 707 ).
- Th2 type cytokines shifting the Th1/Th2 immune balance toward Th2 bias IL-4, IL-5, IL-10 are known, but their administration of itself causes the appearance of systemic side-effects, and clinical application of itself is therefore believed to be substantially impossible.
- NKT cells are lymphocytes which express both NK cell markers (i.e., NKT receptors) and T-cell antigen receptors (TCR). T-cells recognize peptides bonded to major histocompatibility complexes (MHC), while NKT cells recognize glycolipids bonded to the CD1d molecules and produce a large amount of cytokines in an extremely short period of time, when stimulated from TCR.
- NK cell markers i.e., NKT receptors
- TCR T-cell antigen receptors
- the (2S,3S,4R)-1-O-( ⁇ -D-galactosyl)-2-(N-hexacosanoylamino)-1,3,4-octadecanetriol ( ⁇ -GalCer) having the formula (XIV): is the first substance reported, as a ligand presented by the monomorphic CD1d expressed on dendritic cells and activating the NKT cells expressing T-cell receptors having semi-invariant ⁇ -chains (V ⁇ 14). It has been shown that it has a powerful antitumor activity and immunization action (see T. Kawano et al., Proc. Natl. Acad. Sci. USA 1998, 95, p5690 .
- OCH effected in oral administration in a mouse experimental autoimmunological encephalomyelitis (EAE) model, and therefore, so is expected to be a new medicine in the area of autoimmune diseases.
- EAE autoimmunological encephalomyelitis
- the Wittig reaction is in general used for constructing the carbon chain of the sphingosine base part (see M. Morita et al., J. Med. Chem. 1995, 38, 2176 ).
- the glycolipid having the formula (I) is a derivative, in which the carbon chain of the sphingosine base of ⁇ -GalCer is shortened, and therefore, so similar synthetic procedures like with ⁇ -GalCer proved to give low yields. Further, the glycolipid having the formula (I) was originally obtained by purification using ion exchange resin or HPLC, then converting into freeze dried materials.
- large-scale facilities are required at the time of large-scale synthesis, and therefore, not only is there a problem of synthetic costs, there is also the major problem that the quality of the products may not be stable. Therefore, an efficient synthetic method for the large-scale production of the compounds having the formula (I) has not been known yet.
- the synthesis of a glycolipid where the substituent of the sphingosine base part is a substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, or substituted or unsubstituted aralkyl group has not yet been reported.
- the objectives of the present invention are to provide novel glycolipids having an immunosuppressive action useful for the treatment of autoimmune diseases.
- glycolipids may be provided in good quality improved in physical properties.
- glycolipids having formula (I) wherein R 3 indicates a substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, or substituted or unsubstituted aralkyl group, R 8 indicates -(CH 2 ) m -CH 3 where m is from 10 to 25, substituted or unsubstituted C 6 to C 35 aryl group, or substituted or unsubstituted C 3 to C 35 aralkyl group according to claim 1, where the substituent of the Sphingosine base part is a substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, or substituted or unsubstituted aralkyl group, and hydrates of the glycolipids having the formula (I). The hydrates give stable crystals improved in physical properties.
- a novel glycolipid having the above formula (I) where R 3 indicates a substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, or substituted or unsubstituted aralkyl group, and R 8 indicates -(CH 2 )m-CH 3 , where m indicates an integer of 10 to 25, a C 6 to C 35 aryl group unsubstituted or substituted with an alkyl group, alkoxy group, or amide group, or a C 7 to C 35 aralkyl group unsubstituted or substituted with an alkyl group, alkoxy group, or amide group.
- Th2-type cytokine derivative comprising the compound as active ingredient (claim 4), the compound or drug for the treatment of autoimmune disease (claim 5), or the compound or drug for the treatment of diseases where the Th1/Th2 immune balance is shifted toward Th1 bias or diseases where the Th1 cells cause symptoms to worsen (claims 6, 8), or the compound or drug for the treatment of the typical autoimmune diseases mentioned previously (claims 7, 9).
- the "Th2 type cytokine” is IL-4, IL-5, IL-10, or another cytokine, by which the Th1/Th2 immune balance is shifted toward Th2 bias.
- a glycolipid of the invention having the formula (I) may be synthesized by the methods explained below. These methods will be successively explained.
- the starting substance (II), as shown by the reaction formulae below, is obtained by obtaining, from a known starting substance (XV), the compound (XVI), then converting this to the compound (XVII) to obtain the compound (II) (Step 1).
- This compound (II) is reacted with an organometallic reagent (IIIa), (IIIb), (IIIc) or (IIId) to obtain the compound (IV) (Step 2), which is then converted through the compound (V) to the compound (VIa) or (VIb) (Step 3). From these compounds (VIab), the compound (VII) is obtained, then is converted to the compound (VIIIa) or (VIIIb) (Step 4).
- this compound (VIIIa) or (VIIIb) is reacted with the compound (IX) to obtain the compound (Xa) or (Xb) (Step 5), compound (XIa) or (XIb) is obtained from the compound (Xa) or (Xb), then converted to the compound (XIIa) or (XIIb) (Step 6), then the compound (XIIa) is used to derive the compound (XIII).
- This or the compound (XIIb) obtained at Step 6 is used to obtain the target compound (I) (Step 7).
- R 1 and R 2 independently indicate a hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted aryl group, or substituted or unsubstituted aralkyl group or R 1 and R 2 bond together to indicate a propylene group, butylene group, pentylene group or hexylene group, whereby a cyclic structure is formed and R 9 indicates an alkylsulfonyloxy group, arylsulfonyloxy group or aralkylsulfonyloxy group.
- a C 1 to C 4 alkyl group a C 1 to C 4 alkyl group, halogen-substituted methyl group, or other C 1 to C 4 alkyl group (as a preferable, halogen, a fluorine atom or chlorine atom) may be mentioned.
- a preferable substituent of the alkyl group in addition to a halogen atom, a methoxy group, ethoxy group, nitro group, etc. may be mentioned.
- a C 6 to C 12 aryl group specifically a phenyl group, p-tolyl group, m-tolyl group, o-tolyl group, 4-tert-butylphenyl group, 4-phenylphenyl group, 4-isopropylphenyl group, etc. may be mentioned. These may be substituted with a fluorine atom, chlorine atom, bromine atom, methoxy group, nitro group, cyano group, trifluoromethyl group or other group.
- a 4-methoxyphenyl group 4-chlorophenyl group, 2,5-dichlorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 4-nitrophenyl group, 3-nitrophenyl group, 2-nitrophenyl group, 4-cyano group, 4-trifluoromethyl group, etc. may be mentioned.
- the D-arabitol having the formula (XV) enables the production of the compound of formula (XVI) using an acetalization reaction.
- the various methods described in Compendium of Organic Synthetic Methods Wiley-Interscience; A Division of John Wiely & Sons ) etc.
- the compound (XVI) obtained by the above method may be directly used, as a material for producing the compound (XVII), but may also be used, if necessary, after purification by a general purification method, for example, recrystallization or column chromatography.
- the compound (XVII) obtained by the above method may be directly used, as a material for producing the compound (II), but may also be used, if necessary, after purification by a general purification method, for example, recrystallization or column chromatography.
- the compound (XVII) may be treated in tetrahydrofuran, dioxane, ethyleneglycol dimethylether, benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide or another inert solvent at, for example, -20°C to 120°C, preferably -10°C to 80°C, by sodium, potassium, sodium hydride, potassium hydride, sodium methoxide, sodium ethylate, potassium tert-butoxide or another base, so as to obtain the compound (II).
- the compound (II) obtained by this step may be directly used, as a material for the next step, but may also be used, if necessary, after purification by a general purification method such as recrystallization or column chromatography.
- the compound of formula (II) obtained at Step 1 may be reacted with an organometallic reagent having the formula (IIIa), (IIIb), (IIIc), or (IIId) to obtain the compound having the formula (IV).
- R 1 and R 2 are the same as defined above
- R 3 indicates a substituted or unsubstituted preferably C 3 to C 8 cycloalkyl group, for example, a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group or cycloheptyl group (as a preferable substituent, a methyl group, ethyl group, propyl group, butyl group, methoxy group, chlorine atom, fluorine atom, trifluoromethyl group, etc.
- substituted or unsubstituted preferably C 6 to C 18 aryl group for example, a phenyl group, pyridyl group, or naphthyl group (as a preferable substituent, a methyl group, ethyl group, methoxy group, fluorine atom, chlorine atom, phenyl group, 2-fluorophenyl group, phenoxy group, phenylmethyl group, cyclopentyl group, cyclopentyloxy group, trifluoromethyl group, acylamino group, cyano group, cycloheptyl group, cycloheptyloxy group, etc.
- substituted or unsubstituted preferably C 7 to C 18 aralkyl group for example, a phenylmethyl group, phenylethyl group, pyridylmethyl group, or naphthylmethyl group (as a preferable substituent, a fluorine atom, chlorine atom, methyl group, ethyl group, methoxy group, trifluoromethyl group, cyclopentyl group, cyclopentyloxy group, etc. may be mentioned
- M indicates a Li
- MgI and X indicates a chlorine atom, bromine atom, iodine atom or fluorine atom.
- 1 to 6 equivalent weights of alkyl lithium reagent or Grignard reagent is added to the compound (II) in the presence or absence of copper (I) iodide, copper (I) bromide, copper (I) chloride, or borofluoride in diethyl ether, tetrahydrofuran, dioxane, toluene, xylene, hexane, cyclohexane, or another inert solvent or their mixed solvents, at, for example, -78°C to 0°C, preferably -50°C to -10°C and the result stirred at that temperature for 1 to 5 hours.
- the target compound (IV) can be obtained.
- the compound (IV) obtained by this step may be directly used, as a material for production of the compound (V), but may also be used, if necessary, after purification by a general purification method such as recrystallization or column chromatography.
- the compound having the formula (IV) obtained at Step 2 may be converted to the compound (V), then subjected to an azidation reaction so as to obtain the compound having the formula (VIa).
- the compound (V) may be deacetalized to obtain the compound having the formula (VIb).
- R 1 , R 2 and R 3 are the same as defined above and R 4 indicates an alkylsulfonyloxy group, arylsulfonyloxy group or aralkylsulfonyloxy group.
- the compound (IV) obtained by this step may be directly used, as a material for production of the compound (V), but may also be used, if necessary, after purification by a general purification method such as recrystallization or column chromatography.
- the compound (V) by reacting the compound (V) with 1 to 50 equivalent weights of sodium azide or lithium azide in acetonitrile, diethylether, tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylsulfoxide, dimethylformamide or another inert solvent at, for example, 0 to 200°C, preferably 20 to 120°C, the compound (V) can be converted to the compound (VI).
- triethylamine, diisopropylethylamine, pyridine, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate or another base may be added.
- the compound (V) may be deacetalized by an ordinary method to obtain the compound (VIa).
- an ordinary method for the conditions of the deacetalization, it is possible to use the many methods described in Protective Groups In Organic Synthesis (John Wiley & Sons ) etc.
- the compound (V) may be stirred in a mixture of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid or another inorganic acid or another organic acid and methanol, ethanol, 2-propanol, dioxane, methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene or another inert solvent at -20 to 100°C, preferably 0 to 50°C to obtain the compound (VIa).
- the substituent of one or both of R 1 and R 2 expresses a substitutable aryl group
- the compound of formula (VIa) obtained at Step 3 may be deacetalized or the compound of formula (VIb) may be subjected to an azidation reaction to obtain the compound (VII) which may then be again acetalized to obtain the compound of the formula (VIIIa). Further, the primary hydroxy groups of the compound (VII) may be selectively tritylated, then the remaining hydroxy groups are converted to an arylmethylether derivative and detritylated to obtain the compound (VIIIb).
- R 5 and R 6 independently indicate a hydrogen atom, substituted or unsubstituted preferably C 1 to C 5 alkyl group (as a preferable substituent, a fluorine atom, methoxy group, etc. may be mentioned), substituted or unsubstituted C 6 to C 12 aryl group (for example, a phenyl group, p-tolyl group, m-tolyl group, or naphthyl group), substituted or unsubstituted preferably C 7 to C 12 aralkyl group (as a preferable substituent, a methyl group, ethyl group, fluorine atom, methoxy group, etc.
- R 5 and R 6 bond together to indicate a propylene group, butylene group or pentylene group, whereby a cyclic structure is formed, and R 7 indicates a benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, p-nitrobenzyl group, diphenylmethyl group or di(p-nitrophenyl)methyl group.
- the compound (VIa) is deacetalized by an ordinary method to obtain the compound (VII).
- the conditions for the deacetalization it is possible to use the many methods described in Protective Groups In Organic Synthesis (John Wiley & Sons ) etc.
- the compound (VI) may be stirred in a mixture of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid or another inorganic acid or organic acid and methanol, ethanol, 2-propanol, dioxane, methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene or another inert solvent at, for example, -10°C to 100°C, preferably 0 to 50°C to obtain the compound (VII).
- the compound (VIb) may be subjected to an azidation reaction similar to the conversion of the compound (V) to the compound (VIa) of Step 3 to obtain a compound having the formula (VII). That is, the compound (VIb) may be reacted in acetonitrile, diethylether, tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylsulfoxide, dimethylformamide or another inert solvent with 1 to 50 equivalent weights of sodium azide or lithium azide at 0 to 200°C, preferably 20 to 120°C to obtain the compound (VII). At this time, in the reaction, if necessary, triethylamine, diisopropylethylamine, pyridine, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, or another base may also be added.
- the compound (VII) obtained by this reaction may be directly used, as a material for production of the compound (VIIIa) or (VIIIb), but may also be used, if necessary, after purification by a general purification method such as recrystallization or column chromatography.
- the compound (VII) may be subjected to an acetalization reaction to obtain the compound (VIIIa).
- the many methods described in Protective Groups In Organic Synthesis John Wiley & Sons ) etc. may be used. That is, the compound (VII) may be reacted with an acetalization agent in the presence of an organic acid or inorganic acid under non-solvent conditions or in diethylether, dioxane, benzene, toluene, xylene or another inert solvent at, for example, 0 to 200°C, preferably 20 to 120°C to obtain the compound (VIIIa).
- acetalization reagent acetone, 2,2-dimethoxypropane, 2-methoxypropene, 2-ethoxypropene, benzaldehyde, benzaldehyde dimethyl acetal, cyclohexanone, cyclohexanone dimethyl acetal, cyclopentanone, cyclopentanone dimethyl acetal, etc. may be used.
- the primary hydroxy groups of the compound (VII) may be tritylized, then the other secondary hydroxy groups arylmethylated, then detritylized to obtain the compound (VIIIb).
- the conditions for the tritylization for example, 0.8 to 2 equivalent weights of trityl bromide or trityl chloride may be reacted in diethylether, tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide or another inert solvent in the presence of lithium carbonate, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium, potassium, triethylamine, diisopropylethylamine, pyridine, Lutidine or another base at, for example, -50°C to 120°C, preferably -20°C to
- arylmethylation agent benzyl chloride, benzyl bromide, p-methoxybenzyl chloride, m-methoxybenzyl chloride, p-nitrobenzyl chloride, p-nitrobenzyl bromide, etc.
- reaction condition of the arylmethylation the conditions of the above tritylization may be used.
- detritylization it is possible to use the many methods described in Protective Groups In Organic Synthesis (John Wiley & Sons ) etc.
- the compound (VIIIa) or (VIIIb) obtained by the above reaction may be directly used, as a material for producing the compound (Xa) or (Xb), but may also be used, if necessary, after purification by a general purification method, for example, recrystallization or column chromatography.
- the compound having the formula (VIIIa) or (VIIIb) obtained at Step 4 may be subjected to a glycosidation reaction with the compound (IX) to obtain the compound (Xa)or (Xb).
- R 3 , R 5 , R 6 , R 7 and X are the same as defined above.
- the compound (VIIIa) or (VIIIb) may be reacted with the compound (IX) in hexane, cyclohexane, methylene chloride, chloroform, 1,2-dichloroethane, ether, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, dioxane, dimethylformamide or another inert solvent or their mixtures in the presence of boron trifluoride, silver perchlorate, tin (II) chloride, titanium tetrachloride, tin tetrachloride or another Lewis acid or tetra-n-butylammonium bromide or another halogenated ammonium salt at, for example, -100°C to 50°C, preferably -78°C to 30°C to obtain the compound (Xa) or (Xb).
- the Lewis acid or halogenated ammonium salt used for this reaction may be used alone
- the compound (Xa) or (Xb) obtained by the above reaction may be directly used, as a material for the next step, but may also be used, if necessary, after purification by a general purification method, for example, recrystallization or column chromatography.
- the azide group of the compound having the formula (Xa) or (Xb) obtained at Step 5 may be reduced to an amino group to obtain the compound (XIa) or (XIb), then the compound subjected to an amidation reaction with a carboxylic acid derivative to obtain the compound (XIIa) or (XIIb).
- R 3 , R 5 , R 6 , R 7 and X are the same as defined above, and R 8 is a group according to the claims.
- the compound (Xa) or (Xb) may be treated by zinc/hydrochloric acid, lithium aluminum hydride or another metal reagent or triphenylphosphine, trimethylphosphine, triethylphosphine, tributylphosphine or other triarylphosphine or trialkylphosphine or hydrogenated in the presence of Pd-C, Pd-CaCO 3 -Pb, Pd-BaSO 4 , PtO 2 etc. at room temperature to convert it to the compound (XIa) or (XIb).
- the compound (XIa) or (XIb) obtained may be subjected to an amidation reaction with a carboxylic acid to derive the compound (XIIa) or (XIIb).
- the amidation reaction used may be one of the many reactions described in Compendium for Organic Synthesis (Wiley-Interscience; A Division of John Wiley & Sons ) etc.
- the compound (XIa) or (XIb) may be reacted with a corresponding carboxylic acid in methylene chloride, chloroform, 1,2-dichloroethane, diethylether, tetrahydrofuran, dioxane, acetonitrile, benzene, toluene, xylene, dimethylformamide or another inert solvent in the presence of a carboxylic acid activating agent at, for example, -50°C to 120°C, preferably -20°C to 80°C, so as to obtain the compound (XIIa) or (XIIb).
- a carboxylic acid activating agent at, for example, -50°C to 120°C, preferably -20°C to 80°C, so as to obtain the compound (XIIa) or (XIIb).
- carboxylic acid activating reagent silicon tetrachloride, acetic anhydride, acetyl chloride, ethyl chlorocarbonate, 2-iodo-1-methylpyridinium iodide, 2-chloro-1-methylpyridinium iodide, diphenylphosphinylchloride, N,N'-dicyclohexylcarbodiimide (DCC), N-hydroxybenzotriazole/DCC, 1-ethyl-3-(3-diethylaminopropyl)carbodiimide hydrochloride, ethoxyacetylene, trimethylsilylethoxyacetylene, carbodiimidazole, diphenylphosphorylazide, diethylphosphorylcyanidate, etc.
- DCC N,N'-dicyclohexylcarbodiimide
- DCC N-hydroxybenzotriazole/DCC
- p-toluene sulfonic acid polyphosphoric acid or another acid or triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 2,6-Lutidine or another base may be added.
- the compound (XIa) or (XIb) obtained by the above reaction may be directly used, as a material for the next step, but may also be used, if necessary, after purification by a general purification method, for example, recrystallization or column chromatography.
- the compound having the formula (XIIa) obtained at Step 6 may be deacetalized to obtain the compound (XIII) which may then be dearylmethylated to obtain the compound (I). Further, the compound of formula (XIIb) may also be dearylmethylated to similarly obtain the compound (I).
- R 3 , R 5 , R 6 , R 7 and R 8 are the same as defined above.
- the conditions of the deacetalization and dearylmethylation it is possible to use the many methods described in Protective Groups In Organic Synthesis (John Wiley & Sons ) etc.
- this may be performed by the method shown in Step 4.
- the conditions of the dearylmethylation heating and refluxing in methanol, ethanol, 2-propanol, ethyl acetate, tetrahydrofuran, dimethylformamide or another solvent not participating in the reaction in the presence of Pd-C, Pd(OH) 2 , PtO 2 , etc. with the addition of 4-methylcyclohexene or hydrogenating at room temperature may be mentioned.
- the compound (XIIa) obtained by the above reaction may be directly used, as a material for producing the compound (XIII), but may also be used, if necessary, after purification by a general purification method, for example, recrystallization or column chromatography. Further, the compound (I) obtained by this reaction may as required be purification by a general purification method such as recrystallization or column chromatography.
- a glycolipid having the formula (I) of the present invention is low in toxicity.
- a test administering compound 107 to 5-week old mice all 10 subjects administered intraperitoneally doses of 300 ⁇ g/kg twice a week for 4 months survived.
- the yield is low, and therefore, this cannot be used as a practical method of synthesis.
- An addition reaction to an epoxy intermediate using an organometallic reagent may be used to efficiently introduce the carbon chain of the Sphingosine base part.
- compound 107 does not exhibit a clear melting point, but gradually melts at 120°C or more and does not exhibit crystallinity even in differential scan calorimetry (DSC) or powder X-ray crystallography, but it is learned that a hydrate of compound 107, that is, compound 129, has a melting point of 142 to 145°C and exhibits clear crystallinity in differential scan calorimetry (DSC) or powder X-ray crystallography. That is, it is possible to stably supply uniform quality products in large volumes.
- the glycolipid (I) of the present invention may be administered alone, but if desired, may be prepared into a target preparation along with another usual pharmacologically acceptable vehicle. That is, the glycolipid (I) may be administered alone, as an active ingredient, or together with a general excipient in a suitable form such as a capsule, tablet, injection, etc. orally or parenterally.
- the dosage of the drug for treatment of a disease where the Th1/Th2 immune balance is shifted toward the Th1 bias or a disease where the Th1 cells cause the symptoms to worsen or Th2 type cytokine producing derivative of the present invention depends on the patient's condition and age, the route of administration, the form of the drug, the number of times of adminstration, etc., but usually is 0.001 mg to 5000 mg/day/person, preferably 0.01 mg to 500 mg/day/person.
- the compound 2 and a 2.0M benzylmagnesium chloride/tetrahydrofuran solution were used for the same procedure as with synthesis of the compound 3 to obtain the above-referenced compound.
- the compound 2 and a 1.0M cyclopentylmagnesium bromide/tetrahydrofuran solution were used for the same procedure as with synthesis of the compound 3 to obtain the above-referenced compound.
- the compound 2 and a 1.0M p-tolylmagnesium bromide/diethylether solution were used for the same procedure as with synthesis of the compound 3 to obtain the above-referenced compound.
- Example 6 The compound 8 synthesized in Example 6 was used for the same procedure as in Example 10 to obtain the above-referenced compound.
- Example 7 The compound 9 synthesized in Example 7 was used for the same procedure as in Example 10 to obtain the above-referenced compound.
- Example 8 The compound 10 synthesized in Example 8 was used for the same procedure as in Example 10 to obtain the above-referenced compound.
- Example 15 The compound 17 synthesized in Example 15 was used for the same procedure as in Example 19 to obtain the above-referenced compound.
- Example 16 The compound 18 synthesized in Example 16 was used for the same procedure as in Example 19 to obtain the above-referenced compound.
- Example 17 The compound 19 synthesized in Example 17 was used for the same procedure as in Example 19 to obtain the above-referenced compound.
- Example 24 The compound 26 synthesized in Example 24 was used for the same procedure as in Example 28 to obtain the above-referenced compound.
- Example 25 The compound 27 synthesized in Example 25 was used for the same procedure as in Example 28 to obtain the above-referenced compound.
- Example 26 The compound 28 synthesized in Example 26 was used for the same procedure as in Example 28 to obtain the above-referenced compound.
- Example 35 The compound 35 synthesized in Example 33 was used for the same procedure as in Example 39 to obtain the above-referenced compound.
- Example 34 The compound 36 synthesized in Example 34 was used for the same procedure as in Example 39 to obtain the above-referenced compound.
- Example 35 The compound 37 synthesized in Example 35 was used for the same procedure as in Example 39 to obtain the above-referenced compound.
- Example 44 The compound 45 synthesized in Example 44 was used for the same procedure as in Example 47 to obtain the above-referenced compound.
- Example 54 Synthesis of 5-cyclopentyl-2-azido-1-O-(2,3,4,6-tetra-O-benzyl- ⁇ -D-galactopyranosyl)-3,4-O-isopropylidene-D-ribo-1,3,4-pentanetriol (Compound 54)
- Example 45 The compound 46 synthesized in Example 45 was used for the same procedure as in Example 47 to obtain the above-referenced compound.
- Example 47 The compound 47 synthesized in Example 46 was used for the same procedure as in Example 47 to obtain the above-referenced compound.
- Example 60 Synthesis of 6-phenyl-2-amino-1-O-(2,3,4,6-tetra-O-benzyl- ⁇ -D-galactopyranosyl)-3,4-O-isopropylidene-D-ribo-1,3,4-hexanetriol (Compound 60)
- Example 53 The compound 53 synthesized in Example 53 was used for the same procedure as in Example 56 to obtain the above-referenced compound.
- Example 61 Synthesis of 5-cyclopentyl-2-amino-1-O-(2,3,4,6-tetra-O-benzyl- ⁇ -D-galactopyranosyl)-3,4-O-isopropylidene-D-ribo-1,3,4-pentanetriol (Compound 61)
- Example 54 The compound 54 synthesized in Example 54 was used for the same procedure as in Example 56 to obtain the above-referenced compound.
- Example 62 Synthesis of 5-(4-methylphenyl)-2-amino-1-O-(2,3,4,6-tetra-O-benzyl- ⁇ -D-galactopyranosyl)-3,4-O-isopropylidene-D-ribo-1,3,4-pentanetriol (Compound 62)
- Example 55 The compound 55 synthesized in Example 55 was used for the same procedure as in Example 56 to obtain the above-referenced compound.
- Example 71 Synthesis of 6-phenyl-2-tetracosanoylamino-1-O-(2,3,4,6-tetra-O-benzyl- ⁇ -D-galactopyranosyl)-3,4-O-isopropylidene-D-ribo-1,3,4-hexanetriol (Compound 71)
- Example 60 The compound 60 synthesized in Example 60 and n-tetracosanic acid were used for the same procedure as in Example 63 to obtain the above-referenced compound.
- Example 72 Synthesis of 5-cyclopentyl-2-tetracosanoylamino-1-O-(2,3,4,6-tetra-O-benzyl- ⁇ -D-galactopyranosyl)-3,4-O-isopropylidene-D-ribo-1,3,4-pentanetriol (Compound 72)
- Example 61 The compound 61 synthesized in Example 61 and n-tetracosanic acid were used for the same procedure as in Example 63 to obtain the above-referenced compound.
- Example 73 Synthesis of 5-(4-methylphenyl)-2-tetracosanoylamirio-1-O-(2;3,4,6-tetra-O-benzyl- ⁇ -D-galactopyranosyl)-3,4-O-isopropylidene-D-ribo-1,3,4-pentanetriol (Compound 73)
- Example 62 The compound 62 synthesized in Example 62 and n-tetracosanic acid were used for the same procedure as in Example 63 to obtain the above-referenced compound.
- Example 71 The compound 71 synthesized in Example 71 was used for the same procedure as in Example 85 to obtain the above-referenced compound.
- Example 72 The compound 72 synthesized in Example 72 was used for the same procedure as in Example 85 to obtain the above-referenced compound.
- Example 73 The compound 73 synthesized in Example 73 was used for the same procedure as in Example 85 to obtain the above-referenced compound.
- Example 85 To a solution of the compound 85 synthesized in Example 85 (70 mg, 0.66 mmol) in a methanol (3 ml)/chloroform (1 ml), palladium hydroxide (25 mg) was added under a stream of nitrogen. The mixture was stirred at room temperature for 3 hours to hydrogenate it. The catalyst was filtered off, and the filtrate was concentrated in vacuo to quantitatively obtain the above-referenced compound (46 mg).
- Example 93 The compound 93 synthesized in Example 93 was used for the same procedure as in Example 107 to obtain the above-referenced compound.
- Example 94 The compound 94 synthesized in Example 94 was used for the same procedure as in Example 107 to obtain the above-referenced compound.
- Example 95 The compound 95 synthesized in Example 95 was used for the same procedure as in Example 107 to obtain the above-referenced compound.
- Splenocytes were prepared from the spleens of C57BL/6 mice (6 to 8 weeks old, female) and suspended in a RPMI1640 medium (purchased by Nakarai) containing 10% fetal bovine serum (purchased by GIBCO), 5x10- 5 M 2-mercaptoethanol (purchased by GIBCO), 1 mM pyruvate (purchased by SIGMA), and 25 mM HEPE (purchased by SIGMA). These were seeded on a 96-well flat bottom plate (purchased by IWAKI) in an amount of 5x10e5 cells/well and a glycolipid derivative was added to each at a final concentration of 100 ng/ml.
- glycolipid derivatives where the substituent of the Sphingosine base part is a substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, or substituted or unsubstituted aralkyl group, these can be mass produced economically and efficiently.
- Drugs containing these as active ingredients for the treatment of diseases where the Th1/Th2 immune balance is shifted toward the Th1 bias or diseases where the Th1 cells cause the symptoms to worsen or Th2 type cytokine producing derivatives are provided. Further, intermediates useful for the production of these compounds are also provided.
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Abstract
Description
- The present invention relates to novel glycolipid derivatives.
- Autoimmune diseases, both for visceral organ or neuronal cells, are defined as "diseases where the destruction of one's own cells triggers the production of one's own antibodies against the destroyed cells or their ingredients and the destruction by one's own leucocytes is continued". Further, as typical autoimmune diseases, for example, multiple sclerosis, myasthenia gravis, chronic rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, systemic scleroderma, insulin-dependent diabetes, idiopathic thrombocytopenic purpura, Hashimoto's thyroiditis, Basedow's disease (Graves' disease), pernicious anemia, Addison's disease, atrophic gastritis, hemolytic anemia, ulcerative colitis, etc. are known.
- For treatment of autoimmune diseases, steroid hormones, immunosuppressants, etc. are widely used, but at the time of use, sufficient cautions are required over side-effects. Safety and highly effective drug has not yet been found. On the other hand, regarding the cause of autoimmune diseases, the involvement of T-cells has been pointed out. This is believed to arise when the helper T-cell type 1 (Th1)/helper T-cell type 2 (Th2) immune balance is lost. For example, it has been reported that before the relapse of one of the autoimmune diseases, multiple sclerosis, the production of the Th1 type cytokines IFN-γ, IL-12, etc. is observed and that the administration of IFN-γ increases the frequency of relapse of multiple sclerosis. That is, in conditions of multiple sclerosis and other autoimmune diseases, the shift of the Th1/Th2 immune balance toward Th1 bias may be considered to play a central role (P. Kidd, Altern. Med. Rev. 2003, 8, 223: Takashi Yamamura, Notoshinkei, 2001, 53, 707). On the other hand, as Th2 type cytokines shifting the Th1/Th2 immune balance toward Th2 bias, IL-4, IL-5, IL-10 are known, but their administration of itself causes the appearance of systemic side-effects, and clinical application of itself is therefore believed to be substantially impossible.
- NKT cells are lymphocytes which express both NK cell markers (i.e., NKT receptors) and T-cell antigen receptors (TCR). T-cells recognize peptides bonded to major histocompatibility complexes (MHC), while NKT cells recognize glycolipids bonded to the CD1d molecules and produce a large amount of cytokines in an extremely short period of time, when stimulated from TCR.
- For example, the (2S,3S,4R)-1-O-(α-D-galactosyl)-2-(N-hexacosanoylamino)-1,3,4-octadecanetriol (α-GalCer) having the formula (XIV):
WO93/05055 EP0609437 ) andWO98/44928 EP0988860 ). Recently the novel glycolipid OCH discovered by Yamamura et al. is a derivative in which the carbon chain of the sphingosine base part of α-GalCer is shortened and a ligand which similarly bonds to CD1d to stimulate the NKT cells, but α-GalCer causes NKT cells to produce IFN-γ and IL-4, while OCH more selectively promotes the production of IL-4 and shifts the Th1/Th2 immune balance toward Th2 bias (see K. Miyamoto et al., Nature 2001, 413, 531). Further, OCH effected in oral administration in a mouse experimental autoimmunological encephalomyelitis (EAE) model, and therefore, so is expected to be a new medicine in the area of autoimmune diseases. For the synthetic method of glycolipids as represented by α-GalCer, the Wittig reaction, as the key step, is in general used for constructing the carbon chain of the sphingosine base part (see M. Morita et al., J. Med. Chem. 1995, 38, 2176). However, the glycolipid having the formula (I) is a derivative, in which the carbon chain of the sphingosine base of α-GalCer is shortened, and therefore, so similar synthetic procedures like with α-GalCer proved to give low yields. Further, the glycolipid having the formula (I) was originally obtained by purification using ion exchange resin or HPLC, then converting into freeze dried materials. However, by the above method, large-scale facilities are required at the time of large-scale synthesis, and therefore, not only is there a problem of synthetic costs, there is also the major problem that the quality of the products may not be stable. Therefore, an efficient synthetic method for the large-scale production of the compounds having the formula (I) has not been known yet. Further, the synthesis of a glycolipid, where the substituent of the sphingosine base part is a substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, or substituted or unsubstituted aralkyl group has not yet been reported. - Under the above background, the objectives of the present invention are to provide novel glycolipids having an immunosuppressive action useful for the treatment of autoimmune diseases.
- These glycolipids may be provided in good quality improved in physical properties.
- The inventors succeeded in the efficient synthesis of glycolipids having formula (I):
- Compounds of the present invention are defined in claim 1. They may be provided by a synthetic method of a glycolipid derivative comprising:
- reacting a compound having the formula (II):
- reacting the compound having the formula (V) with an azidation agent to obtain a compound having the formula (VIa) :
- removing the protective acetal group of the compound having the formula (VIa) or removing the protective acetal group of the compound having the formula (V) to obtain a compound of the formula (VIb):
reacting with the compound having the formula (VIb) with an azidation agent to obtain a compound having the formula (VII):
again acetalizing the compound having the formula (VII) to obtain a compound having the formula (VIIIa): - protecting the two secondary hydroxy groups of the compound having the formula (VII) to obtain a compound having the formula (VIIIb):
- reacting the compound having the above formula (VIIIa) or (VIIIb) with a compound having the formula (IX) :
- reducing the azide group of the compound having the formula (Xa)or (Xb) to an amino group to obtain a compound having the formula (XIa)or (XIb):
- acylating the amino group of the compound having the formula (XIa) or (XIb) to obtain a compound having the formula (XIIa) or (XIIb):
- removing the remaining protective groups of the compound having the above formula (XIIb) or (XIII) to obtain a compound having the formula (I):
- In accordance with the present invention (claim 1) there is provided a novel glycolipid having the above formula (I) where R3 indicates a substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, or substituted or unsubstituted aralkyl group, and R8 indicates -(CH2)m-CH3, where m indicates an integer of 10 to 25, a C6 to C35 aryl group unsubstituted or substituted with an alkyl group, alkoxy group, or amide group, or a C7 to C35 aralkyl group unsubstituted or substituted with an alkyl group, alkoxy group, or amide group.
- Further aspects are a drug or Th2-type cytokine derivative comprising the compound as active ingredient (claim 4), the compound or drug for the treatment of autoimmune disease (claim 5), or the compound or drug for the treatment of diseases where the Th1/Th2 immune balance is shifted toward Th1 bias or diseases where the Th1 cells cause symptoms to worsen (claims 6, 8), or the compound or drug for the treatment of the typical autoimmune diseases mentioned previously (claims 7, 9). The "Th2 type cytokine" is IL-4, IL-5, IL-10, or another cytokine, by which the Th1/Th2 immune balance is shifted toward Th2 bias.
- A glycolipid of the invention having the formula (I) may be synthesized by the methods explained below. These methods will be successively explained.
- First, the starting substance (II), as shown by the reaction formulae below, is obtained by obtaining, from a known starting substance (XV), the compound (XVI), then converting this to the compound (XVII) to obtain the compound (II) (Step 1). This compound (II) is reacted with an organometallic reagent (IIIa), (IIIb), (IIIc) or (IIId) to obtain the compound (IV) (Step 2), which is then converted through the compound (V) to the compound (VIa) or (VIb) (Step 3). From these compounds (VIab), the compound (VII) is obtained, then is converted to the compound (VIIIa) or (VIIIb) (Step 4). Next, this compound (VIIIa) or (VIIIb) is reacted with the compound (IX) to obtain the compound (Xa) or (Xb) (Step 5), compound (XIa) or (XIb) is obtained from the compound (Xa) or (Xb), then converted to the compound (XIIa) or (XIIb) (Step 6), then the compound (XIIa) is used to derive the compound (XIII). This or the compound (XIIb) obtained at Step 6 is used to obtain the target compound (I) (Step 7). These Step 1 to Step 7 will now be explained in detail.
- It is possible to synthesize the compound having the formula (II) from the known starting material D-arabitol (XV).
- In the above reaction, the D-arabitol having the formula (XV) enables the production of the compound of formula (XVI) using an acetalization reaction. For the synthesis of the compound (XVI), it is possible to use the various methods described in Compendium of Organic Synthetic Methods (Wiley-Interscience; A Division of John Wiely & Sons) etc. If giving one example, it is possible to use the method of reacting the compound (XV) in benzene, toluene, dioxane, chloroform, or another solvent not participating in the reaction at, for example, -20°C to 100°C, preferably 0 to 80°C, in the presence of 1 to 30 equivalent weights of acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or another organic acid or hydrochloric acid, sulfuric acid, nitric acid, or another inorganic acid with acetoaldehyde, propionaldehyde, butylaldehyde, pentanal, cyclopentanone, cyclohexanone, phenylacetoaldehyde, benzaldehyde, p-tolualdehyde, 4-fluorobenzaldehyde, 2-naphthylaldehyde, etc.
- The compound (XVI) obtained by the above method may be directly used, as a material for producing the compound (XVII), but may also be used, if necessary, after purification by a general purification method, for example, recrystallization or column chromatography.
- Then, by reacting the compound (XVI) in methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, diethylether, tetrahydrofuran, dioxane, benzene, toluene, xylene, ethyl acetate or another inert solvent in the presence of triethylamine, diisopropylethylamine, pyridine, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate or another base at, for example, -20°C to 100°C, preferably -10°C to 80°C, with 1 to 5 equivalent weights of methanesulfonyl chloride, methanesulfonic acid anhydride, ethane sulfonyl chloride, 1-propanesulfonyl chloride, 1-butanesulfonyl chloride, trifluoromethanesulfonyl chloride, α-toluene sulfonyl chloride, benzene sulfonyl chloride, p-toluene sulfonyl chloride, m-toluene sulfonyl chloride, o-toluene sulfonyl chloride, p-toluene sulfonic acid anhydride, 4-methoxybenzene sulfonyl chloride, 4-chlorobenzene sulfonyl chloride, 2,5-dichlorobenzene sulfonyl chloride, 4-bromobenzene sulfonyl chloride, 4-fluorobenzene sulfonyl chloride, 2-nitrobenzene sulfonyl fluoride, 3-nitrobenzene sulfonyl chloride, 4-nitrobenzene sulfonyl chloride, 4-tert-butylbenzene sulfonyl chloride, 2-nitro-α-toluene sulfonyl chloride, α-toluene sulfonyl fluoride, or another sulfonylation agent for 1 to 72 hours, the compound (XVII) can be obtained. At this time, surprisingly, it was learned that, by adding a catalytic amount (for example, 0.01 to 2 moles, based upon 1 mol of the compound (XVI)) of di-n-butyl tin oxide, the primary hydroxy groups having the compound (XVI) are selectively sulfonylated and the reaction proceeds in a short time.
- The compound (XVII) obtained by the above method may be directly used, as a material for producing the compound (II), but may also be used, if necessary, after purification by a general purification method, for example, recrystallization or column chromatography.
- The compound (XVII) may be treated in tetrahydrofuran, dioxane, ethyleneglycol dimethylether, benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide or another inert solvent at, for example, -20°C to 120°C, preferably -10°C to 80°C, by sodium, potassium, sodium hydride, potassium hydride, sodium methoxide, sodium ethylate, potassium tert-butoxide or another base, so as to obtain the compound (II).
- The compound (II) obtained by this step may be directly used, as a material for the next step, but may also be used, if necessary, after purification by a general purification method such as recrystallization or column chromatography.
- The compound of formula (II) obtained at Step 1 may be reacted with an organometallic reagent having the formula (IIIa), (IIIb), (IIIc), or (IIId) to obtain the compound having the formula (IV).
- That is, 1 to 6 equivalent weights of alkyl lithium reagent or Grignard reagent is added to the compound (II) in the presence or absence of copper (I) iodide, copper (I) bromide, copper (I) chloride, or borofluoride in diethyl ether, tetrahydrofuran, dioxane, toluene, xylene, hexane, cyclohexane, or another inert solvent or their mixed solvents, at, for example, -78°C to 0°C, preferably -50°C to -10°C and the result stirred at that temperature for 1 to 5 hours. By adding the compound (II) into this and further stirring for 1 to 5 hours, the target compound (IV) can be obtained.
- The compound (IV) obtained by this step may be directly used, as a material for production of the compound (V), but may also be used, if necessary, after purification by a general purification method such as recrystallization or column chromatography.
- The compound having the formula (IV) obtained at Step 2 may be converted to the compound (V), then subjected to an azidation reaction so as to obtain the compound having the formula (VIa).
-
- By reacting the compound (IV) under non-solvent conditions or in methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, diethylether, tetrahydrofuran, dioxane, benzene, toluene, xylene, ethyl acetate or another inert solvent at, for example, -20°C to 100°C, preferably -10°C to 80°C, in the presence of triethylamine, diisopropylethylamine, pyridine, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, or another base with 1 to 5 equivalent weights of methanesulfonyl chloride, methanesulfonic acid anhydride, ethane sulfonyl chloride, 1-propanesulfonyl chloride, 1-butanesulfonyl chloride, trifluoromethanesulfonyl chloride, α-toluene sulfonyl chloride, benzene sulfonyl chloride, p-toluene sulfonyl chloride, p-toluene sulfonic acid anhydride, 4-methoxybenzene sulfonyl chloride, 4-chlorobenzene sulfonyl chloride, 2-nitrobenzene sulfonyl chloride, 3-nitrobenzene sulfonyl chloride, 4-nitrobenzene sulfonyl chloride, 2-nitro-α-toluene sulfonyl chloride, α-toluene sulfonyl fluoride or another sulfonylization agent, for example, for 1 to 72 hours, compound (V) can be obtained.
- The compound (IV) obtained by this step may be directly used, as a material for production of the compound (V), but may also be used, if necessary, after purification by a general purification method such as recrystallization or column chromatography.
- Then, by reacting the compound (V) with 1 to 50 equivalent weights of sodium azide or lithium azide in acetonitrile, diethylether, tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylsulfoxide, dimethylformamide or another inert solvent at, for example, 0 to 200°C, preferably 20 to 120°C, the compound (V) can be converted to the compound (VI). At this time, in this reaction, if necessary, triethylamine, diisopropylethylamine, pyridine, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate or another base may be added.
- Further, the compound (V) may be deacetalized by an ordinary method to obtain the compound (VIa). For the conditions of the deacetalization, it is possible to use the many methods described in Protective Groups In Organic Synthesis (John Wiley & Sons) etc. For example, the compound (V) may be stirred in a mixture of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid or another inorganic acid or another organic acid and methanol, ethanol, 2-propanol, dioxane, methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene or another inert solvent at -20 to 100°C, preferably 0 to 50°C to obtain the compound (VIa). Further, when, in the compound (V), the substituent of one or both of R1 and R2 expresses a substitutable aryl group, it is possible to heat and reflux this in methanol, ethanol, 2-propanol, ethyl acetate, tetrahydrofuran, dimethylformamide or another solvent not participating in the reaction in the presence of Pd-C, Pd(OH)2, PtO2, etc. with the addition of 4-methylcyclohexene or hydrogenate this at room temperature to obtain the compound (VIa).
- The compound of formula (VIa) obtained at Step 3 may be deacetalized or the compound of formula (VIb) may be subjected to an azidation reaction to obtain the compound (VII) which may then be again acetalized to obtain the compound of the formula (VIIIa). Further, the primary hydroxy groups of the compound (VII) may be selectively tritylated, then the remaining hydroxy groups are converted to an arylmethylether derivative and detritylated to obtain the compound (VIIIb).
- First, the compound (VIa) is deacetalized by an ordinary method to obtain the compound (VII). For the conditions for the deacetalization, it is possible to use the many methods described in Protective Groups In Organic Synthesis (John Wiley & Sons) etc. For example, the compound (VI) may be stirred in a mixture of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid or another inorganic acid or organic acid and methanol, ethanol, 2-propanol, dioxane, methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene or another inert solvent at, for example, -10°C to 100°C, preferably 0 to 50°C to obtain the compound (VII).
- Further, the compound (VIb) may be subjected to an azidation reaction similar to the conversion of the compound (V) to the compound (VIa) of Step 3 to obtain a compound having the formula (VII). That is, the compound (VIb) may be reacted in acetonitrile, diethylether, tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylsulfoxide, dimethylformamide or another inert solvent with 1 to 50 equivalent weights of sodium azide or lithium azide at 0 to 200°C, preferably 20 to 120°C to obtain the compound (VII). At this time, in the reaction, if necessary, triethylamine, diisopropylethylamine, pyridine, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, or another base may also be added.
- The compound (VII) obtained by this reaction may be directly used, as a material for production of the compound (VIIIa) or (VIIIb), but may also be used, if necessary, after purification by a general purification method such as recrystallization or column chromatography.
- Then, the compound (VII) may be subjected to an acetalization reaction to obtain the compound (VIIIa). For the conditions for the acetalization, the many methods described in Protective Groups In Organic Synthesis (John Wiley & Sons) etc. may be used. That is, the compound (VII) may be reacted with an acetalization agent in the presence of an organic acid or inorganic acid under non-solvent conditions or in diethylether, dioxane, benzene, toluene, xylene or another inert solvent at, for example, 0 to 200°C, preferably 20 to 120°C to obtain the compound (VIIIa). At this time, as the acetalization reagent, acetone, 2,2-dimethoxypropane, 2-methoxypropene, 2-ethoxypropene, benzaldehyde, benzaldehyde dimethyl acetal, cyclohexanone, cyclohexanone dimethyl acetal, cyclopentanone, cyclopentanone dimethyl acetal, etc. may be used.
- Further, the primary hydroxy groups of the compound (VII) may be tritylized, then the other secondary hydroxy groups arylmethylated, then detritylized to obtain the compound (VIIIb). As the conditions for the tritylization, for example, 0.8 to 2 equivalent weights of trityl bromide or trityl chloride may be reacted in diethylether, tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide or another inert solvent in the presence of lithium carbonate, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium, potassium, triethylamine, diisopropylethylamine, pyridine, Lutidine or another base at, for example, -50°C to 120°C, preferably -20°C to 80°C as a condition. Further, as the arylmethylation agent, benzyl chloride, benzyl bromide, p-methoxybenzyl chloride, m-methoxybenzyl chloride, p-nitrobenzyl chloride, p-nitrobenzyl bromide, etc. may be mentioned, while as the reaction condition of the arylmethylation, the conditions of the above tritylization may be used. Further, for the conditions of the detritylization, it is possible to use the many methods described in Protective Groups In Organic Synthesis (John Wiley & Sons) etc. For example, reaction under non-solvent conditions or in methylene chloride, chloroform, 1,2-dichloroethane, benzene, toluene, xylene, dioxane, water, methanol, ethanol, 2-propanol, tert-butanol or another solvent in the presence of formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, nitric acid or another acid or cupric sulfate at, for example, -50°C to 150°C, preferably -20°C to 100°C may be mentioned.
- The compound (VIIIa) or (VIIIb) obtained by the above reaction may be directly used, as a material for producing the compound (Xa) or (Xb), but may also be used, if necessary, after purification by a general purification method, for example, recrystallization or column chromatography.
-
- That is, the compound (VIIIa) or (VIIIb) may be reacted with the compound (IX) in hexane, cyclohexane, methylene chloride, chloroform, 1,2-dichloroethane, ether, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, dioxane, dimethylformamide or another inert solvent or their mixtures in the presence of boron trifluoride, silver perchlorate, tin (II) chloride, titanium tetrachloride, tin tetrachloride or another Lewis acid or tetra-n-butylammonium bromide or another halogenated ammonium salt at, for example, -100°C to 50°C, preferably -78°C to 30°C to obtain the compound (Xa) or (Xb). The Lewis acid or halogenated ammonium salt used for this reaction may be used alone or in combinations with different types. Further, at that time, if necessary, a molecular sieve may also be added.
- The compound (Xa) or (Xb) obtained by the above reaction may be directly used, as a material for the next step, but may also be used, if necessary, after purification by a general purification method, for example, recrystallization or column chromatography.
- The azide group of the compound having the formula (Xa) or (Xb) obtained at Step 5 may be reduced to an amino group to obtain the compound (XIa) or (XIb), then the compound subjected to an amidation reaction with a carboxylic acid derivative to obtain the compound (XIIa) or (XIIb).
- First, in the reaction for selectively reducing the azide group to an amide group, the compound (Xa) or (Xb) may be treated by zinc/hydrochloric acid, lithium aluminum hydride or another metal reagent or triphenylphosphine, trimethylphosphine, triethylphosphine, tributylphosphine or other triarylphosphine or trialkylphosphine or hydrogenated in the presence of Pd-C, Pd-CaCO3-Pb, Pd-BaSO4, PtO2 etc. at room temperature to convert it to the compound (XIa) or (XIb).
- Then, the compound (XIa) or (XIb) obtained may be subjected to an amidation reaction with a carboxylic acid to derive the compound (XIIa) or (XIIb). The amidation reaction used may be one of the many reactions described in Compendium for Organic Synthesis (Wiley-Interscience; A Division of John Wiley & Sons) etc. Giving one example, the compound (XIa) or (XIb) may be reacted with a corresponding carboxylic acid in methylene chloride, chloroform, 1,2-dichloroethane, diethylether, tetrahydrofuran, dioxane, acetonitrile, benzene, toluene, xylene, dimethylformamide or another inert solvent in the presence of a carboxylic acid activating agent at, for example, -50°C to 120°C, preferably -20°C to 80°C, so as to obtain the compound (XIIa) or (XIIb). As the carboxylic acid activating reagent, silicon tetrachloride, acetic anhydride, acetyl chloride, ethyl chlorocarbonate, 2-iodo-1-methylpyridinium iodide, 2-chloro-1-methylpyridinium iodide, diphenylphosphinylchloride, N,N'-dicyclohexylcarbodiimide (DCC), N-hydroxybenzotriazole/DCC, 1-ethyl-3-(3-diethylaminopropyl)carbodiimide hydrochloride, ethoxyacetylene, trimethylsilylethoxyacetylene, carbodiimidazole, diphenylphosphorylazide, diethylphosphorylcyanidate, etc. may be mentioned. Further, if necessary, p-toluene sulfonic acid, polyphosphoric acid or another acid or triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 2,6-Lutidine or another base may be added.
- The compound (XIa) or (XIb) obtained by the above reaction may be directly used, as a material for the next step, but may also be used, if necessary, after purification by a general purification method, for example, recrystallization or column chromatography.
- The compound having the formula (XIIa) obtained at Step 6 may be deacetalized to obtain the compound (XIII) which may then be dearylmethylated to obtain the compound (I). Further, the compound of formula (XIIb) may also be dearylmethylated to similarly obtain the compound (I).
- For the conditions of the deacetalization and dearylmethylation, it is possible to use the many methods described in Protective Groups In Organic Synthesis (John Wiley & Sons) etc. For example, as the conditions for the deacetalization, this may be performed by the method shown in Step 4. Further, as the conditions of the dearylmethylation, heating and refluxing in methanol, ethanol, 2-propanol, ethyl acetate, tetrahydrofuran, dimethylformamide or another solvent not participating in the reaction in the presence of Pd-C, Pd(OH)2, PtO2, etc. with the addition of 4-methylcyclohexene or hydrogenating at room temperature may be mentioned.
- The compound (XIIa) obtained by the above reaction may be directly used, as a material for producing the compound (XIII), but may also be used, if necessary, after purification by a general purification method, for example, recrystallization or column chromatography. Further, the compound (I) obtained by this reaction may as required be purification by a general purification method such as recrystallization or column chromatography.
- A glycolipid having the formula (I) of the present invention where R3 indicates a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group, R8 indicates -(CH2)m-CH3, where m is an integer of 10 to 25, a C6 to C35 aryl group unsubstituted or substituted with an alkyl group, alkoxy group, or amide group, or a C7 to C35 arakyl group unsubstituted or substituted with an alkyl group, alkoxy group, amide group and a hydrate of a glycolipid having the formula (I), wherein R3 indicates substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, or substituted or unsubstituted aralkyl group, and R8 indicates -(CH2)m-CH3, where m indicates an integer of 10 to 25 are useful, as active ingredients of drugs for the treatment of diseases where the Th1/Th2 immune balance is eccentric to the Th1 or diseases where the Th1 cells cause symptoms to worsen and also are useful as active ingredients for Th2 type cytokine producing derivatives.
- A glycolipid having the formula (I) of the present invention is low in toxicity. For example, in a test administering compound 107 to 5-week old mice, all 10 subjects administered intraperitoneally doses of 300 µg/kg twice a week for 4 months survived. In the production of the compound (I), when conducting the step of introducing a carbon chain of the Sphingosine base part in the same way as the conventional α-GalCer by a Wittig reaction, the yield is low, and therefore, this cannot be used as a practical method of synthesis. An addition reaction to an epoxy intermediate using an organometallic reagent may be used to efficiently introduce the carbon chain of the Sphingosine base part. It is therefore possible to simply produce, at a high yield, a glycolipid where the substituent of the Sphingosine base part of formula (I) is a substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group or substituted or unsubstituted aralkyl group. Further, in the hydrate of the glycolipid having the formula (I) of the present invention, improvements in the physical properties and quality were seen. For example, compound 107 does not exhibit a clear melting point, but gradually melts at 120°C or more and does not exhibit crystallinity even in differential scan calorimetry (DSC) or powder X-ray crystallography, but it is learned that a hydrate of compound 107, that is, compound 129, has a melting point of 142 to 145°C and exhibits clear crystallinity in differential scan calorimetry (DSC) or powder X-ray crystallography. That is, it is possible to stably supply uniform quality products in large volumes. The glycolipid (I) of the present invention may be administered alone, but if desired, may be prepared into a target preparation along with another usual pharmacologically acceptable vehicle. That is, the glycolipid (I) may be administered alone, as an active ingredient, or together with a general excipient in a suitable form such as a capsule, tablet, injection, etc. orally or parenterally.
- The dosage of the drug for treatment of a disease where the Th1/Th2 immune balance is shifted toward the Th1 bias or a disease where the Th1 cells cause the symptoms to worsen or Th2 type cytokine producing derivative of the present invention depends on the patient's condition and age, the route of administration, the form of the drug, the number of times of adminstration, etc., but usually is 0.001 mg to 5000 mg/day/person, preferably 0.01 mg to 500 mg/day/person.
- The present invention will now be explained in further detail based on Reference Examples and Examples of the invention, but the scope of the present invention is by no means limited to these Examples.
- To 1,3-O-benzylidene-D-arabitol able to be synthesized from D-arabitol and benzaldehyde (R. Wild et al., Liebigs Ann. Org. Bioorg. Chem. 1995, 5, 755-764) (34.0 g, 141 mmol) in a methylene chloride (1.2L) suspension, under ice cooling, dibutyl tin oxide (702 mg, 2.82 mmol) and p-toluene sulfonyl chloride (27.0 g, 141 mmol) were added in small amounts at a time. Further, triethylamine (19.7 ml, 141 mmol) was added. The mixture was stirred at 0°C to room temperature for 21 hours. The reaction mixture was concentrated, then the residue obtained was purified by silica gel column chromatography (methylene chloride:methanol=20:1)to obtain the above-referenced compound in an amount of 55.3 g (yield 99%).
- To the compound 1 synthesized in Reference Example 1 (51.1 g, 130 mmol) in a dehydrated tetrahydrofuran (800 ml) solution, under ice cooling, potassium t-butoxide (18.1 g, 161 mmol) was added. The resultant mixture was stirred at 0°C to room temperature for 38 hours. Water was added to the reaction mixture, then the product was extracted with ethyl acetate (3 times) and washed with brine. The organic layer was dried with sodium sulfate, then filtered and concentrated in vacuo. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the above-referenced compound in an amount of 26.2 g (yield 92%).
- To copper (I) iodide (42.9 g, 225 mmol) in a dehydrated tetrahydrofuran (560 ml) suspension, 2.64M n-butyl lithium/n-hexane solution (341 ml, 900 mmol) was dropwise added at -40°C and the mixture stirred at -30°C to -10°C for 30 minutes to 2 hours. Next, the compound 2 synthesized as shown in Example 2 (50.0 g, 225 mmol) in a dehydrated tetrahydrofuran (400 ml) solution was dropwise added at -40°C and the resultant mixture stirred at -30°C to -20°C for about 3 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, the product was extracted with ethyl acetate, and the organic layer was washed with brine, dried with magnesium sulfate, filtered, then concentrated in vacuo to obtain the above-referenced compound 58.4g (yield 93%).
- The compound 2 and a 2.0M benzylmagnesium chloride/tetrahydrofuran solution were used for the same procedure as with synthesis of the compound 3 to obtain the above-referenced compound.
- The compound 2 and a 1.0M cyclopentylmagnesium bromide/tetrahydrofuran solution were used for the same procedure as with synthesis of the compound 3 to obtain the above-referenced compound.
- The compound 2 and a 1.0M p-tolylmagnesium bromide/diethylether solution were used for the same procedure as with synthesis of the compound 3 to obtain the above-referenced compound.
- To a dehydrated pyridine (142 ml) solution of the compound 3 synthesized in Example 1 (3.90 g, 13.9 mmol), methanesulfonyl chloride (1.05 ml) was dropwise added at -40°C. The reaction mixture was stirred at -40°C to -30°C for 5 hours and at room temperature over night. The reaction mixture was concentrated, then toluene was used for azeotropic removal of pyridine (2 times), then the residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:2) to obtain the above-referenced compound in an amount of 4.65 g (yield 93%).
- The compound 8 synthesized in Example 6 was used for the same procedure as in Example 10 to obtain the above-referenced compound.
- The compound 9 synthesized in Example 7 was used for the same procedure as in Example 10 to obtain the above-referenced compound.
- The compound 10 synthesized in Example 8 was used for the same procedure as in Example 10 to obtain the above-referenced compound.
- To the compound 12 synthesized at Example 10 (4.60 g, 12.8 mmol) in a dehydrated dimethylformamide (128 ml) solution, sodium azide (10.0g) was added. The mixture was stirred at 110°C for 7 hours. Water was added to the reaction mixture, the product was extracted with ethyl acetate, and the organic layer was washed with brine (2 times), was dried with sodium sulfate, filtered, then concentrated in vacuo. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:1) to obtain the above-referenced compound in an amount of 1.53 g (yield 39%).
- The compound 17 synthesized in Example 15 was used for the same procedure as in Example 19 to obtain the above-referenced compound.
- The compound 18 synthesized in Example 16 was used for the same procedure as in Example 19 to obtain the above-referenced compound.
- The compound 19 synthesized in Example 17 was used for the same procedure as in Example 19 to obtain the above-referenced compound.
- To the compound 21 synthesized in Example 19 (11.4 g, 37.3 mmol) in a methanol (180 ml) solution, under ice cooling, 6N hydrochloric acid aqueous solution (17.8 ml) was added. The mixture was stirred at room temperature over night. The reaction mixture was neutralized with triethylamine or potassium carbonate, then was concentrated in vacuo. The residue obtained was purified by silica gel column chromatography (methylene chloride:methanol=15:1) to obtain the above-referenced compound in an amount of 6.1 g (yield 79%).
- The compound 26 synthesized in Example 24 was used for the same procedure as in Example 28 to obtain the above-referenced compound.
- The compound 27 synthesized in Example 25 was used for the same procedure as in Example 28 to obtain the above-referenced compound.
- The compound 28 synthesized in Example 26 was used for the same procedure as in Example 28 to obtain the above-referenced compound.
- To the compound 30 synthesized in Example 28 (4.00 g, 18.4 mmol) in a dimethoxypropane (73 ml) solution, under ice cooling, p-toluene sulfonic acid-hydrate (175 mg, 0.92 mmol) was added and the mixture stirred at room temperature for 2 hours. Next, methanol was added to the reaction mixture, the mixture was stirred at room temperature for 1 hour, then the reaction mixture was concentrated in vacuo. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the above-referenced compound in an amount of 3.61 g (yield 75%).
- The compound 35 synthesized in Example 33 was used for the same procedure as in Example 39 to obtain the above-referenced compound.
- The compound 36 synthesized in Example 34 was used for the same procedure as in Example 39 to obtain the above-referenced compound.
- The compound 37 synthesized in Example 35 was used for the same procedure as in Example 39 to obtain the above-referenced compound.
- To dried molecular sieve (4A, powder) (1.96 g), the compound 40 synthesized in Example 39 (431 mg, 1.68 mmol) and 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl fluoride (Hayashi et al., Chem. Lett. 1984, 1747) (1.22 g, 2.26 mmol) in dehydrated chloroform (39 ml) solution was added and the mixture was stirred at room temperature for 30 minutes. Then, boron trifluoride-ether complex (201 µl, 1.59 mmol) in dehydrated chloroform (7 ml) was dropwise added at -50°C and the reaction mixture was stirred at - 50°C to -30°C for 6 hours and at 0°C over night. The molecular sieve was filtered off, then a saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture. The product was extracted with chloroform, and the organic layer was dried using magnesium sulfate, filtered, then concentrated in vacuo. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1 to 5:1) to obtain the above-referenced compound in an amount of 712 mg (yield 57%).
- The compound 45 synthesized in Example 44 was used for the same procedure as in Example 47 to obtain the above-referenced compound.
- The compound 46 synthesized in Example 45 was used for the same procedure as in Example 47 to obtain the above-referenced compound.
- The compound 47 synthesized in Example 46 was used for the same procedure as in Example 47 to obtain the above-referenced compound.
- To the compound 48 synthesized in Example 47 (2.58 g, 3.31 mmol) in an ethanol (260 ml) solution, palladium-calcium carbonate (lead poisoned) (Lindlar catalyst)(2.60 g) was added. The mixture was stirred at ordinary pressure at room temperature over night for hydrogenation. The catalyst was filtered off, then the filtrate was concentrated in vacuo to obtain the above-referenced compound 2.46 g (yield 99%).
- The compound 53 synthesized in Example 53 was used for the same procedure as in Example 56 to obtain the above-referenced compound.
- The compound 54 synthesized in Example 54 was used for the same procedure as in Example 56 to obtain the above-referenced compound.
- The compound 55 synthesized in Example 55 was used for the same procedure as in Example 56 to obtain the above-referenced compound.
- To n-tetracosanic acid (1.22 g, 3.31 mmol) in a suspension of dimethylformamide (90 ml) and methylene chloride (210 ml), under ice cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (761 mg, 3.97 mmol) and 1-hydroxybenzotriazole (536 mg, 3.97 mmol) were added and the mixture was stirred at room temperature for 30 minutes. Then, to the reaction mixture, the compound 56 synthesized in Example 56 (2.46 g, 3.26 mmol) and N,N-diisopropylethylamine (1.38 ml, 7.97 mmol) in a methylene chloride (120 ml) solution were added and the mixture was stirred at 30°C over night. The reaction solution was diluted with a mixed solvent of ethyl acetate/diethylether=4/1, then was washed with a saturated sodium hydrogen carbonate aqueous solution, 1N hydrochloric acid, water, and brine. The organic layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 to 3:1) to obtain the above-referenced compound in an amount of 3.25 g (yield 89%).
- The compound 60 synthesized in Example 60 and n-tetracosanic acid were used for the same procedure as in Example 63 to obtain the above-referenced compound.
- The compound 61 synthesized in Example 61 and n-tetracosanic acid were used for the same procedure as in Example 63 to obtain the above-referenced compound.
- The compound 62 synthesized in Example 62 and n-tetracosanic acid were used for the same procedure as in Example 63 to obtain the above-referenced compound.
- A solution of the compound 63 synthesized in Example 63 (89 mg, 0.081 mmol) in a methanol (1 ml)/methylene chloride (5 ml)/4N hydrochloric acid-dioxane (100µl) was stirred at room temperature for 2 hours, then concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1) to obtain the above-referenced compound 70 mg (yield 82%). Further, the above-referenced compound could also be obtained by stirring the compound 63 in an 80% acetic acid aqueous solution at 45°C over night, then concentrating the reaction mixture in vacuo.
- The compound 71 synthesized in Example 71 was used for the same procedure as in Example 85 to obtain the above-referenced compound.
- The compound 72 synthesized in Example 72 was used for the same procedure as in Example 85 to obtain the above-referenced compound.
- The compound 73 synthesized in Example 73 was used for the same procedure as in Example 85 to obtain the above-referenced compound.
- To a solution of the compound 85 synthesized in Example 85 (70 mg, 0.66 mmol) in a methanol (3 ml)/chloroform (1 ml), palladium hydroxide (25 mg) was added under a stream of nitrogen. The mixture was stirred at room temperature for 3 hours to hydrogenate it. The catalyst was filtered off, and the filtrate was concentrated in vacuo to quantitatively obtain the above-referenced compound (46 mg).
- The compound 93 synthesized in Example 93 was used for the same procedure as in Example 107 to obtain the above-referenced compound.
- The compound 94 synthesized in Example 94 was used for the same procedure as in Example 107 to obtain the above-referenced compound.
- The compound 95 synthesized in Example 95 was used for the same procedure as in Example 107 to obtain the above-referenced compound.
- The physicochemical data obtained in the above Reference Example and Examples are shown in Table I.
Table I Comp. no. Chemical structure Rf value MS 1H-NMR (CDCl3) 1 0.37 (CH2Cl2:MeOH= 20:1) 395 (M+H) (ESI) 7.80 (d, 2H, J=8.2Hz), 7.40-7.36 (m, 5H), 7.30 (d, 2H, J=8.2Hz), 5.50 (s, 1H), 4.31-4.21 (m, 3H), 4.15-4.07 (m, 2H), 3.90-3.83 (m, 2H), 2.75-2.67 (m, 2H), 2.41 (s, 3H) 2 0.28 (Hex:AcOEt= 1:2) 223 (M+H) (ESI) 7.52-7.49 (m, 2H), 7.41-7.37 (m, 3H), 5.57 (s, 1H), 4.26 (dd, 1H, J=12, 1.5Hz), 4.09 (dd, 1H, J=12, 1.5Hz), 3.79-3.76 (m, 2H), 3.35-3.32 (m, 1H), 2.93-2.85 (m, 3H) 3 0.37 (Hex:AcOEt= 1:1) 281(M+H) (FAB) 7.52-7.50 (m, 2H), 7.42-7.38 (m, 3H), 5.60 (s, 1H), 4.28 (dd, 1H, J=12, 1.8Hz), 4.05 (dd, 1H, J=12, 1.3Hz), 3.95-3.88 (m, 2H), 3.71 (dd, 1H, J=6.6, 1.3Hz), 3.25 (d, 1H, J=8.7Hz), 2.34 (d, 1H, J=4.5Hz), 1.73-1.53 (m, 2H), 1.40-1.30 (m, 6H), 0.90 (t, 3H, J=6.7Hz) 5 0.13 (Hex:AcOEt= 1:1) 275 (M+Na) (ESI) 7.51-7.48 (m, 2H), 7.40-7.35 (m, 3H), 5.58 (s, 1H), 4.26 (dd, 1H, J=12, 1.9Hz), 4.03 (dd, 1H, J=12, 1.3Hz), 3.95-3.86 (m, 2H), 3.68 (dd, 1H, J=6.6, 1.3Hz), 3.26 (d, 1H, J=8.7Hz), 2.39 (d, 1H, J=4.6Hz), 1.70-1.39 (m, 4H), 0.95 (t, 3H, J=7.1Hz) 8 0.19 (Hex:AcOEt= 2:1) 337 (M+Na) (ESI) 7.49-7.46 (m, 2H), 7.39-7.34 (m, 3H), 7.29-7.15 (m, 5H), 5.55 (s, 1H), 4.26 (dd, 1H, J=12, 1.8Hz), 4.03 (dd, 1H, J=12, 1.2Hz), 3.98-3.92 (m, 1H), 3.87 (dd, 1H, J=9.1, 1.3Hz), 3.70 (dd, 1H, J=6.7, 1.1Hz), 3.14 (d, 1H, J=9.1Hz), 2.96-2.88 (m, 1H), 2.75-2.68 (m, 1H), 2.34 (d, 1H, J=4.6Hz), 2.08-1.99 (m, 1H), 1.92-1.82 (m, 1H) 9 0.41 (Hex:AcOEt= 1:1) 315 (M+Na) (ESI) 7.51-7.48 (m, 2H), 7.40-7.35 (m, 3H), 5.58 (s, 1H), 4.26 (dd, 1H, J=12, 1.9Hz), 4.03 (dd, 1H, J=12, 1.4Hz), 4.01-3.95 (m, 1H), 3.89 (dd, 1H, J=8.3, 1.4Hz), 3.68 (dd, 1H, J=6.3, 1.1Hz), 3.29 (d, 1H, J=8.4Hz), 2.31 (d, 1H, J=4.4Hz), 2.08-2.00 (m, 1H), 1.84-1.81 (m, 2H), 1.65-1.53 (m, 6H), 1.21-1.07 (m, 2H) 10 0.58 (Hex:AcOEt= 1:1) 337 (M+Na) (ESI) 7.53 (dd, 2H, J=7.6,2.0Hz), 7.37-7.41 (m, 3H), 7.14 (q, 4H, J=8.0Hz), 5.58 (s, 1H), 4.26 (dd, 1H, J=12,1.8Hz), 4.05 (dd, 1H, J=12,1.2Hz), 3.88(d, 1H, J=8.8Hz), 3.70 (dd, 1H, J=7.7,0.9Hz), 3.08 (dd, 1H, J=14, 3.7Hz), 2.95 (d, 1H, J=10Hz), 2.79-2.72 (m, 1H), 2.33 (s, 3H), 2.11 (d, 1H, J=4.7Hz) 12 0.32 (Hex:AcOEt= 3:2) 359 (M+H) (FAB) 7.51-7.48 (m, 2H), 7.42-7.35 (m, 3H), 5.59 (s, 1H), 4.99 (d, 1H, J=1.4Hz), 4.53 (dd, 1H, J=13, 1.6Hz), 4.18 (dd, 1H, J=13, 1.1Hz), 3.84-3.75 (m, 2H), 3.19 (s, 3H), 1.60-1.27 (m, 8H), 0.90 (t, 3H, J=6.8Hz) 17 0.33 (Hex:AcOEt= 1:1) 415 (M+Na) (ESI) 7.47-7.44 (m, 2H), 7.39-7.34 (m, 3H), 7.29-7.15 (m, 5H), 5.54 (s, 1H), 4.98 (d, 1H, J=1.2Hz), 4.49 (dd, 1H, J=13, 1.5Hz), 4.15 (dd, 1H, J=13, 1.2Hz), 3.86-3.81 (m, 1H), 3.77 (dd, 1H, J=9.0, 1.0Hz), 3.15 (s, 3H), 2.97-2.89 (m, 2H), 2.74-2.66 (m, 1H), 2.18-2.16 (m, 1H), 2.03-1.74 (m, 1H) 18 0.56 (Hex:AcOEt= 1:1) 393 (M+Na) (ESI) 7.49-7.46 (m, 2H), 7.39-7.35 (m, 3H), 5.57 (s, 1H), 4.98 (d, 1H, J=1.3Hz), 4.51 (dd, 1H, J=13, 1.6Hz), 4.15 (dd, 1H, J=13, 1.2Hz), 3.86-3.80 (m, 1H), 3.72 (dd, 1H, J=7.4, 1.3Hz), 3.18 (s, 3H), 2.73 (d, 1H, J=5.5Hz), 2.08-2.03 (m, 1H), 1.83-1.75 (m, 2H), 1.61-1.51 (m, 6H), 1.19-1.03 (m, 2H) 19 0.33 (Hex:AcOEt= 1:1) 415 (M+Na) (ESI) 7.53 (dd, 2H, J=7.7,1.9Hz), 7.49-7.43 (m, 3H), 7.16 (d, 2H, J=8.2Hz), 7.13 (d, 2H, J=8.1Hz), 5.59 (s, 1 H), 4.91 (d, 1H, J=1.3Hz), 4.53 (dd, 1H, J=13, 1.4Hz), 4.12 (dd, 1H, J=13, 0.8Hz), 4.01-4.06 (m, 1H), 3.77 (dd, 1H, J=9.1, 0.8Hz), 3.14 (s, 3 H), 2.78-2.72 (m, 1H), 2.55 (d, 1H, J=7.2Hz), 2.33 (s, 3H). 21 0.41 (Hex:AcOEt= 4:1) 305 (M+Na) (ESI) 7.47-7.37 (m, 5H), 5.49(s, 1H), 4.43-4.40 (m, 1H), 3.93-3.88 (m, 1H), 3.75-3.67 (m, 3H), 2.09 (d, 1H, J=6.2Hz), 1.67-1.59 (m, 2H), 1.43-1.34 (m, 6H), 0.91 (t, 3H, J=6.8Hz) 26 0.39 (Hex:AcOEt= 1:1) 312 (M-N2+H) (ESI) 7.45-7.42 (m, 2H), 7.38-7.36 (m, 3H), 7.31-7.17 (m, 5H), 5.45 (s, 1H), 4.40-4.37 (m, 1H), 3.92-3.89 (m, 1H), 3.73-3.63 (m, 3H), 2.94-2.91 (m, 1H), 2.75-2.71 (m, 1H), 2.20 (d, 1H, J=6.2Hz), 1.99-1.93 (m, 2H) 27 0.58 (Hex:AcOEt= 3:1) 290 (M-N2+H) (ESI) 7.46-7.43 (m, 2H), 7.40-7.36 (m, 3H), 5.47 (s, 1H), 4.39 (dd, 1H, J=9.5, 3.5Hz),, 3.98-3.92 (m, 1H), 3.73-3.66 (m, 3H), 2.10-2.00 (m, 1H), 2.02 (d, 1H, J=6.5Hz), 1.90-1.72 (m, 3H), 1.67-1.49 (m, 5H), 1.21-1.05 (m, 2H) 28 0.47 (Hex:AcOEt= 1:1) 312 (M-N2+H) (ESI) 7.49-7.40(m, 2H), 7.39-7.37 (m, 3H), 7.18 (d, 2H, J=8.0Hz), 7.14 (d, 2H, J=8.0Hz), 5.48 (s, 1H), 4.40 (dd, 1H, J=10,4.5Hz), 4.16-4.13 (m, 1H), 3.77-3.66 (m, 2H), 3.04 (dd, 1H, J=14,4.4Hz), 2.90-2.85 (m, 1H), 2.34 (s, 3H), 2.09 (d, 1H, J=7.2 HZ). 30 0.35 (Hex:AcOEt= 1:1) 218(M+H) (FAB) 4.05-3.98 (m, 1H), 3.91-3.74 (m, 3H), 3.71-3.66 (m, 1H), 2.67 (brs 1H), 2.52 (d, 1H, J=4.4Hz), 2.20 (brs, 1H), 1.61-1.52 (m, 2H), 1.40-1.31 (m, 6H), 0.91 (t, 3H, J=6.6Hz) 35 0.14 (Hex:AcOEt= 1:1) 224 (M-N2+H) (ESI) 7.30-7.16 (m, 5H), 3.96-3.91 (m, 1H), 3.86-3.72 (m, 3H), 3.62-3.57 (m, 1H), 3.17 (brs 1H), 3.08 (d, 1H, J=4.6Hz), 2.90-2.77 (m, 2H), 2.72-2.66 (m, 1H), 1.93-1.81 (m, 2H) 36 0.25 (CH2Cl2:MeOH= 20:1) 252 (M +Na) (ESI) 4.04-3.97 (m, 1H), 3.89-3.85 (m, 2H), 3.75 (m, 1H), 3.66 (m, 1H), 2.66 (m, 1H), 2.49 (d, 1H, J=4.6Hz), 2.17 (d, 1H, J=4.2Hz), 2.04-1.91 (m, 1H), 1.84-1.80 (m, 2H), 1.67-1.49 (m, 6H), 1.21-1.05 (m, 2H) 37 0.10 (Hex:AcOEt= 1:1) 224 (M-N2+H) (ESI) 7.17-7.12 (m, 4H), 4.04-3.93 (m, 2H), 3.84-3.81 (m, 1H), 3.75 (q, 1H, J=4.9Hz), 3.03 (dd, 1H, J=13, 3.3Hz), 2.71 (dd, 1H, J=13, 9.6Hz), 2.34 (s, 3H). 40 0.21 (Hex:AcOEt= 5:1) 280 (M+Na) (ESI) 4.21-4.16 (m, 1H), 4.02-3.95 (m, 2H), 3.90-3.84 (m, 1H), 3.50-3.45 (m, 1H), 2.11 (t, 1H, J=5.6Hz), 1.63-1.54 (m, 2H), 1.43 (s, 3H), 1.40-1.34 (m, 9H), 0.91(t, 3H, J=6.9Hz) 45 0.34 (Hex:AcOEt= 4:1) 264 (M-N2+H) (ESI) 7.31-7.17 (m, 5H), 4.19-4.14 (m, 1H), 4.02-3.94 (m, 2H), 3.89-3.83 (m, 1H), 3.48-3.43 (m, 1H), 2.92-2.88 (m, 1H), 2.74-2.68 (m, 1H), 2.16-2.13 (m, 1H), 1.94-1.85 (m, 2H), 1.46 (s, 3H), 1.34 (s, 3H) 46 0.65 (CH2Cl2:MeOH= 20:1) 242 (M-N2+H) (ESI) 4.26-4.21 (m, 1H), 4.01-3.94 (m, 2H), 3.89-3.83 (m, 1H), 3.48-3.43 (m, 1H), 2.06-1.97 (m, 2H), 1.84-1.82 (m, 2H), 1.72-1.47 (m, 6H), 1.42 (s, 3H), 1.33 (s, 3H), 1.21-1.08 (m, 2H) 47 0.23 (Hex:AcOEr= 4:1) 264 (M-N2+H) (ESI) 7.17 (d, 2H, J=8.0Hz), 7.14 (d, 2H, J=8.0 Hz), 4.46-4.41 (m, 1H), 4.08-4.03 (m, 1H), 3.95-3.89 (m, 1H), 3.63-3.60 (m, 1H), 2.97(dd, 1H, J=14,3.0Hz), 2.78 (dd, 1H, J=14,10Hz), 2.33 (s, 3H)), 2.11 (dd, 1H, J=6.7,5.4Hz), 1.49 (s, 3H), 1.30 (s, 3H). 48 0.43 (Hex:AcOEt= 3:1) 803 (M+Na) (ESI) 7.40-7.26 (m, 20H), 4.97-4.93 (m, 2H), 4.87-4.79 (m, 2H), 4.74-4.70 (m, 2H), 4.57 (d, 1H, J=12Hz), 4.49 (d, 1H, J=12Hz), 4.41 (d, 1H, J=12Hz), 4.10-3.94 (m, 7H), 3.75-3.70 (m, 1H), 3.56-3.44 (m, 3H), 1.62-1.49 (m, 2H), 1.40-1.26 (m, 12H), 0.91 (t, 3H, J=6.6Hz) 53 0.39 (Hex:AcOEt= 5:1) 787 (M-N2+H) (ESI) 7.38-7.18 (m, 25H), 4.95-4.92 (m, 2H), 4.85-4.77 (m, 2H), 4.72-4.67 (m, 2H), 4.56 (d, 1H, J=12Hz), 4.46 (d, 1H, J=12Hz), 4.38 (d, 1H, J=12Hz), 4.13-3.92 (m, 7H), 3.75-3.70 (m, 1H), 3.53-3.44 (m, 3H), 2.91-2.85 (m, 1H), 2.72-2.66 (m, 1H), 1.94-1.84 (m, 2H), 1.41 (s, 3H), 1.28 (s, 3H) 54 0.45 (Hex:AcOEt= 1:1) 764 (M-N2+H) (ESI) 7.38-7.25 (m, 20H), 4.94-4.92 (m, 2H), 4.83 (d, 1H, J=12Hz), 4.78 (d, 1H, J=12Hz), 4.70 (d, 1H, J=12Hz), 4.69 (d, 1H, J=12Hz), 4.55 (d, 1H, J=12Hz), 4.47 (d, 1H, J=12Hz), 4.39 (d, 1H, J=12Hz), 4.17-4.12 (m, 1H), 4.07-3.92 (m, 6H), 3.70 (dd, 1H, J=11, 6.6Hz), 3.50-3.44 (m, 3H), 2.01-1.93 (m, 1H), 1.88-1.75 (m, 2H), 1.68-1.46 (m, 6H), 1.36 (s, 3H), 1.26 (s, 3H), 1.18-1.06 (m, 2H) 55 0.63 (Hex:AcOEt= 3:1) 787 (M-N2+H) (FAB) 7.51-7.24 (m, 20H), 7.14 (d, 2H, J=8.0Hz), 7.10 (d, 2H, J=8.0Hz), 4.96-4.93 (m, 2H), 4.85-4.78 (m, 2H), 4.73-4.69 (m, 2H), 4.56 (d, 1H, J=10Hz), 4.48 (d, 1H, J=13Hz), 4.41 (d, 1H, J=13Hz), 4.38-4.34 (m, 1H), 4.16-3.96 (m, 6H), 3.78-3.74 (m, 1H), 3.63-3.60 (m, 1H), 3.55-3.49 (m, 2H), 2.95 (dd, 1H, J=14, 2.7Hz), 2.77-2.71 (m, 1H), 2.32 (s, 3H), 1.43 (s, 3H), 1.23 (s, 3H). 56 0.28 (CH2Cl2:MeOH =20:1) 754 (M+H) (ESI) 7.40-7.25 (m, 20H), 4.96-4.92 (m, 2H), 4.84-4.64 (m, 4H), 4.58 (d, 1H, J=11 Hz), 4.50 (d, 1H, J=12Hz), 4.41 (d, 1H, J=12Hz), 4.13-3.86 (m, 6H), 3.58-3.51 (m, 2H), 3.42-3.37 (m, 1H), 3.07-3.01 (m, 1H), 1.65-1.20 (m, 14H), 0.90 (t, 3H, J=5.6Hz) 60 0.21 (Hex:AcOEt= 1:1) 788 (M+) (ESI) 7.37-7.14 (m, 25H), 4.94-4.90 (m, 2H), 4.81-4.76 (m, 2H), 4.72 (d, 1H, J=12 Hz), 4.66 (d, 1H, J=12Hz), 4.55 (d, 1H, J=11Hz), 4.44 (d, 1H, J=12Hz), 4.36 (d, 1H, J=12Hz), 4.15-4.08 (m, 1H), 4.05-4.02 (m, 1H), 3.95-3.84 (m, 5H), 3.54-3.49 (m, 2H), 3.40-3.35 (m, 1H), 3.05-3.00 (m, 1H), 2.92-2.86 (m, 1H), 2.68-2.60 (m, 1H), 1.88-1.79 (m, 2H), 1.43 (s, 3H), 1.29 (s, 3H) 61 0.21 (CH2Cl2: MEOH =20:1) 766 (M+H) (FAB) 7.38-7.25 (m, 20H), 4.94-4.91 (m, 2H), 4.82-4.74 (m, 2H), 4.71-4.65 (m, 2H), 4.56 (d, 1H, J=11Hz), 4.46 (d, 1H, J=12Hz), 4.39 (d, 1H, J=12Hz), 4.18-4.13 (m, 1H), 4.04 (dd, 1H, J=10, 3.6Hz), 3.97-3.90 (m, 4H), 3.85 (dd, 1H, J=9.0, 5.5Hz), 3.66-3.49 (m, 2H), 3.37 (dd, 1H, J=10, 7.6Hz), 3.06-3.02 (m, 1H), 2.04-1.93 (m, 1H), 1.87-1.74 (m, 2H), 1.71-1.39 (m, 6H), 1.37 (s, 3H), 1.27 (s, 3H), 1.17-1.00 (m, 2H) 62 0.42 (Hex:AcOEt= 1:1) 788 (M+H) (ESI) 7.25-7.39 (m, 20H), 7.14 (d, 2H, J=8.0Hz), 7.09 (d, 2H, J=8.0Hz), 4.95-4.92 (m, 2H), 4.80-4.55 (m, 5H), 4.48-4.31 (m, 3H), 4.08-3.94 (m, 6H), 3.74-3.55 (m, 4H), 2.95 (dd, 1H, J=14,3.4Hz), 2.74-2.68 (m, 1H), 2.30 (s, 3 H), 1.46 (s, 3H), 1.24 (s, 3H). 63 0.23 (Hex:AcOEt= 4:1) 1105 (M+H) (FAB) 7.41-7.24 (m, 20H), 6.28 (d, 1H, J=8.4Hz), 4.95-4.90 (m, 2H), 4.83-4.73 (m, 2H), 4.75 (d, 1H, J=12Hz), 4.66 (d, 1H, J=11Hz), 4.58 (d, 1H, J=12Hz), 4.49 (d, 1H, J=12Hz), 4.38 (d, 1H, J=12Hz), 4.13-4.03 (m, 4H), 3.98 (t, 1H, J=6.2Hz), 3.93-3.90 (m, 3H), 3.63-3.53 (m, 2H), 3.40-3.37 (m, 1H), 2.08-1.95 (m, 2H), 1.55-1.25 (m, 50H), 1.40 (s, 3H), 1.32 (s, 3H), 0.90-0.84 (m, 6H) 71 0.19 (Hex:AcOEt= 5:1) 1138 (M+) (FAB) 7.38-7.09 (m, 25H), 6.27 (d, 1H, J=8.3Hz), 4.92-4.86 (m, 2H), 4.81-4.76 (m, 2H), 4.72 (d, 1H, J=12 Hz), 4.63 (d, 1H, J=11Hz), 4.55 (d, 1H, J=12Hz), 4.38 (d, 1H, J=12Hz), 4.28 (d, 1H, J=12Hz), 4.09-4.07 (m, 3H), 4.02 (dd, 1H, J=10, 3.7Hz), 3.94 (t, 1H,J=6.2Hz), 3.89-3.85 (m, 3H), 3.60-3.58 (m, 1H), 3.51-3.47 (m, 1H), 3.33-3.29 (m, 1H), 2.85-2.75 (m, 1H), 2.63-2.53 (m, 1H), 2.05-1.88 (m, 2H), 1.86-1.74 (m, 1H), 1.65-1.55 (m, 1H), 1.50-1.43 (m, 5H), 1.30-1.20 (m, 43H), 0.87 (t, 3H, J=6.8Hz) 72 0.20 (Hex:AcOEt= 4:1) 1116 (M+) (FAB) 7.42-7.23 (m, 20H), 6.19 (d, 1H, J=8.3Hz), 4.92-4.89 (m, 2H), 4.80 (d, 1H, J=12Hz), 4.79 (d, 1H, J=11Hz), 4.73 (d, 1H, J=12Hz), 4.64 (d, 1H, J=11Hz), 4.56 (d, 1H, J=12Hz), 4.49 (d, 1H, J=12Hz), 4.36 (d, 1H, J=12Hz), 4.13-3.89 (m, 8H), 3.62-3.60 (m, 1H), 3.54-3.50 (m, 1H), 3.38-3.34 (m, 1H), 2.07-1.89 (m, 3H), 1.77-1.69 (m, 2H), 1.64-1.45 (m, 6H), 1.39 (s, 3H), 1.30 (s, 3H), 1.24-1.22 (m, 42H), 1.11-1.01 (m, 2H), 0.87 (t, 3H, J=6.8Hz) 73 0.42 (Hex:AcOEt= 3:1) 1139 (M+H) (FAB) 7.39-7.22 (m, 20H), 7.05 (d, 2H, J=7.8Hz), 7.00 (d, 2H, J-8.0Hz), 6.40 (d, 1H, J=8.4Hz), 4.94-4.92 (m, 2H), 4.83-4.76 (m, 2H), 4.75-4.72 (m, 1H), 4.66 (d, 1H, J=11Hz), 4.58 (d, 1H, J=11Hz), 4.48 (d, 1H, J=12Hz), 4.29-4.12 (m, 3H), 4.09-4.04 (m, 2H), 3.99-3.96 (m, 1H), 3.93-3.90 (m, 2H), 3.65 (d, 1H, J=11Hz), 3.53 (d, 1H, J=6.8Hz), 3.41-3.37 (m, 1H), 2.68 (d, 1H, J=7.4Hz), 2.29 (s, 3H), 2.09-2.01 (m, 2H), 1.47-1.45 (m, 5H), 1.28-1.23 (m, 43H), 0.88 (t, 3H, J=6.8Hz). 85 0.55 (CH2Cl2:MeOH =20:1) 1064 (M+) (FAB) 7.39-7.27 (m, 20H), 6.38 (d, 1H, J= 8.4Hz), 4.93-4.84 (m, 4H), 4.77-4.76 (m, 1H), 4.68 (d, 1H, J=12Hz), 4.57 (d, 1H, J=11Hz), 4.48 (d, 1H, J=12Hz), 4.39 (d, 1H, J=12Hz), 4.22-4.19 (m, 1H), 4.05(dd, 1H, J=10, 3.8Hz), 3.97 (m, 1H), 3.89-3.85 (m, 4H), 3.80(d, 1H, J=8.3Hz), 3.52-3.44 (m, 3H), 2.14-2.10 (m, 2H), 1.56-1.26 (m, 50H), 0.90-0.87 (m, 6H) 93 0.12 (Hex:AcOEt= 2:1) 1098 (M+) (FAB) 7.37-7.22 (m, 22H), 7.16-7.13 (m, 3H), 6.32 (d, 1H, J= 8.4Hz), 4.90 (d, 1H, J=11Hz), 4.87-4.81 (m, 2H), 4.75-4.73 (m, 1H), 4.64 (d, 1H, J=12Hz), 4.56 (d, 1H, J=11Hz), 4.45 (d, 1H, J=12Hz), 4.36 (d, 1H, J=12Hz), 4.20-4.17 (m, 1H), 4.03 (dd, 1H, J=10, 3.8Hz), 3.94-3.93 (m, 1H), 3.90-3.81 (m, 4H), 3.72 (d, 1H, J=7.8Hz), 3.53-3.42 (m, 4H), 2.80-2.76 (m, 1H), 2.61-2.57 (m, 1H), 2.25 (brs, 1H), 2.08 (t, 2H, J=7.6Hz), 1.92-1.87 (m, 1H), 1.69-1.64 (m, 1H), 1.31-1.20 (m, 42H), 0.87 (t, 3H, J=6.8Hz) 94 0.25 (CH2Cl2:MeOH =20:1) 1076 (M+) (FAB) 7.37-7.25 (m, 20H), 6.35 (d, 1H, J= 8.3Hz), 4.92-4.83 (m, 3H), 4.78-4.71 (m, 2H), 4.66 (d, 1H, J=12Hz), 4.55 (d, 1H, J=11Hz), 4.46 (d, 1H, J=12Hz), 4.37 (d, 1H, J=12Hz), 4.19-4.16 (m, 1H), 4.03 (dd, 1H, J=10, 3.8Hz), 3.95 (m, 1H), 3.84-3.82 (m, 3H), 3.78 (d, 1H, J=8.5Hz), 3.57-3.42 (m, 4H), 3.50 (d, 1H, J=6.4Hz), 2.14-2.08 (m, 3H), 1.93-1.87 (m, 1H), 1.78-1.69 (m, 2H), 1.61-1.42 (m, 6H), 1.34-0.92 (m, 44H), 0.87 (t, 3H, J=6.8Hz) 95 0.10 (CH2Cl2:MeOH =20:1) 1099 (M+H) (FAB) 7.36-7.26 (m, 20H), 7.09 (d, 2H, J=7.4Hz), 7.04 (d, 2H, J=8.0Hz), 6.45 (d, 1H, J=7.8Hz), 4.92-4.88 (m, 2H), 4.85-4.83 (m, 2H), 4.73 (d, 2H, J=3.7Hz), 4.68 (d, 1H, J=7.6Hz), 4.56 (d, 1H, J=11Hz), 4.46 (d, 1H, J=7.6Hz), 4.36 (d, 1H, J=7.7Hz), 4.05-4.02 (m, 1H), 3.94-3.84 (m, 5H), 3.69-3.65 (m, 1H), 3.51-3.48 (m, 3H), 2.31 (s, 3H), 2.10-2.08 (m, 2H), 1.47-1.45 (m, 2H), 1.33-1.22 (m, 40H), 0.88 (t, 3H, J=7.6Hz). 107 0.40 (CH2Cl2: MeOH =5:1) 704(M+) (FAB) 4.91 (brs, 1H), 4.14 (m, 1H), 3.97 (m, 1H), 3.79-3.76 (m, 7H), 3.64-3.63 (m, 2H), 3.52 (m, 1H), 2.14 (t, 2H, J=7.4Hz), 1.61-1.13 (m, 50H), 0.84-0.79 (m, 6H) 115 0.08 (CH2Cl2:MeOH =10:1) 738 (M+) (ESI) 7.45-7.14 (m, 5H), 4.89 (d, 1H, J=3.6Hz), 4.25-4.22 (m, 1H), 3.91-3.85 (m, 2H), 3.81-3.62 (m, 6H), 3.60-3.50 (m, 2H), 2.95-2.85 (m, 1H), 2.73-2.62 (m, 1H), 2.17 (t, 2H, J=7.7Hz), 2.07-1.95 (m, 1H), 1.72-1.53 (m, 3H), 1.33-1.18 (m, 40H), 0.88 (t, 3H, J=6.5Hz) 116 0.36 (CH2Cl2:MeOH =5:1) 717 (M+H) (FAB) 4.78 (d, 1H, J=3.8Hz), 4.08-4.05 (m, 1H), 3.83-3.81 (m, 1H), 3.78-3.74 (dd, 1H, J=11, 4.8Hz), 3.72-3.46 (m, 8H), 3.40-3.37 (m, 1H), 2.07 (t, 2H, J=7.7Hz), 1.94-1.84 (m, 1H), 1.71-1.59 (m, 2H), 1.51-1.42 (m, 6H), 1.19-0.86 (m, 44H), 0.75 (t, 3H, J=6.8Hz) 117 0.30 (CH2Cl2:MeOH =5:1) 738 (M+) (ESI) 6.87 (d, 2H, J=7.9Hz), 6.82 (d, 2H, J=7.8Hz), 4.64 (d, 1H, J=4.0Hz), 4.25-4.22 (m, 1H), 3.92-3.86 (m, 2H), 3.67-3.65 (m, 2H), 3.52-3.43 (m, 7H), 3.40-3.36 (m, 2H), 3.10-3.08 (m, 3H), 2.80-2.78 (m, 1H), 2.35-2.32 (m, 1H), 2.04 (s, 3H), 1.96 (t, 2H, J=7.6Hz), 1.35-1.32 (m, 2H), 1.06-1.00 (m, 40H), 0.62 (t, 3H, J=6.8Hz). - Splenocytes were prepared from the spleens of C57BL/6 mice (6 to 8 weeks old, female) and suspended in a RPMI1640 medium (purchased by Nakarai) containing 10% fetal bovine serum (purchased by GIBCO), 5x10-5M 2-mercaptoethanol (purchased by GIBCO), 1 mM pyruvate (purchased by SIGMA), and 25 mM HEPE (purchased by SIGMA). These were seeded on a 96-well flat bottom plate (purchased by IWAKI) in an amount of 5x10e5 cells/well and a glycolipid derivative was added to each at a final concentration of 100 ng/ml. The results were cultured at 37°C in the presence of 5% CO2 for 72 hours, then the culture supernatent was collected. The concentration of the IL-4 and IFN-γ in the culture supernatent were measured by ELISA (BD Pharmingen EIA Kit) (Table 2).
Table 2 Compound no. IL-4 (pg/ml) IFN-γ (pg/ml) 115 137 2481 116 226 5268 117 181 5485 α -Galcer 201 21900 Control 10 18 - As a result, in the case of α-GalCer, as previously reported, it was confirmed that IFN-γ was produced remarkably dominantly. On the other hand, it was learned that the compounds of the present invention had weaker IFN-γ producing activities compared with α-GalCer and caused IL-4 to be predominantly produced.
- According to the present invention, by chemically synthesizing glycolipid derivatives, where the substituent of the Sphingosine base part is a substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, or substituted or unsubstituted aralkyl group, these can be mass produced economically and efficiently. Drugs containing these as active ingredients for the treatment of diseases where the Th1/Th2 immune balance is shifted toward the Th1 bias or diseases where the Th1 cells cause the symptoms to worsen or Th2 type cytokine producing derivatives are provided. Further, intermediates useful for the production of these compounds are also provided.
Claims (9)
- A compound which is a glycolipid having the formula (I) :
R3 indicates substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, or substituted or unsubstituted aralkyl group, and
R8 indicates -(CH2)m-CH3 where m is from 10 to 25, C6 to C35 aryl group unsubstituted or substituted with an alkyl group, alkoxy group or amide group, or C7 to C35 aralkyl group unsubstituted or substituted with an alkyl group, alkoxy group or amide group; or a hydrate thereof. - A compound of claim 1 which is a said hydrate and wherein in formula (I) R8 indicates said -(CH2)m-CH3, where m is from 10 to 25.
- A compound according to claim 1 or 2 in which R3 is selected from:cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group or cycloheptyl group, either unsubstituted or substituted with methyl group, ethyl group, propyl group, butyl group, methoxy group, chlorine atom, fluorine atom or trifluoromethyl group;phenyl group, pyridyl group or naphthyl group, either unsubstituted or substituted with methyl group, ethyl group, methoxy group, fluorine atom, chlorine atom, phenyl group, 2-fluorophenyl group, phenoxy group, phenylmethyl group, cyclopentyl group, cyclopentyloxy group, trifluoromethyl group, acylamino group, cyano group, cycloheptyl group or cycloheptyloxy group;phenylmethyl group, phenylethyl group, pyridylmethyl group or naphthylmethyl group, either unsubstituted or substituted with fluorine atom, chlorine atom, methyl group, ethyl group, methoxy group, trifluoromethyl group, cyclopentyl group or cyclopentyloxy group.
- A drug or Th2-type cytokine-producing derivative comprising a compound of claim 1, 2 or 3 as active ingredient.
- A compound of claim 1, 2 or 3 or drug of claim 4 for the treatment of autoimmune disease.
- A compound of claim 1, 2 or 3 or drug of claim 4 for the treatment of disease where the Th1/Th2 immune balance is shifted toward the Th1 bias, or of disease where the Th1 cells worsen the symptoms.
- A compound of claim 1, 2 or 3 or drug of claim 4 for the treatment of multiple sclerosis, myasthenia gravis, chronic rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, systemic scleroderma, insulin-dependent diabetes, idiopathic thrombocytopenic purpura, Hashimoto's thyroiditis, Basedow's disease (Graves' disease), pernicious anaemia, Addison's disease, atrophic gastritis, haemolytic anaemia or ulcerative colitis.
- Use of a compound as defined in any one of claims 1 to 3 in the manufacture of a drug for treating disease in which the Th1/Th2 immune balance is shifted towards a Th1 bias, or in which symptoms are worsened by Th1 cells.
- Use according to claim 8 in which the drug is for the treatment of multiple sclerosis, myasthenia gravis, chronic rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, systemic scleroderma, insulin-dependent diabetes, idiopathic thrombocytopenic purpura, Hashimoto's thyroiditis, Basedow's disease (Graves' disease), pernicious anaemia, Addison's disease, atrophic gastritis, haemolytic anaemia or ulcerative colitis.
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ES2450043T3 (en) | 2014-03-21 |
CA2515396A1 (en) | 2004-08-26 |
CN100537585C (en) | 2009-09-09 |
US20100210828A1 (en) | 2010-08-19 |
WO2004072091B1 (en) | 2004-11-11 |
CN101165047B (en) | 2010-10-20 |
JP4742220B2 (en) | 2011-08-10 |
US20060074235A1 (en) | 2006-04-06 |
US7732583B2 (en) | 2010-06-08 |
EP1619199A1 (en) | 2006-01-25 |
US8034908B2 (en) | 2011-10-11 |
JP2011063593A (en) | 2011-03-31 |
EP2343306A1 (en) | 2011-07-13 |
CN101165047A (en) | 2008-04-23 |
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